Melanocortin receptor ligands modified with hydantoin

ABSTRACT

The present invention relates to peptide ligands of the melanocortin receptors, in particular the melancortin-4 receptor, and as such, are useful in the treatment of disorders responsive to the activation of this receptor, such as obesity, diabetes mellitus and sexual dysfunction.

This application is a divisional application filed under 35 U.S.C. §111, claiming priority to U.S. patent application Ser. No. 15/688,959filed Aug. 29, 2017, which is a continuation application filed under 35U.S.C. § 111, claiming priority to U.S. patent application Ser. No.15/055,873 filed Feb. 29, 2016, which issued as U.S. Pat. No. 9,758,549and is a continuation application filed under 35 U.S.C. § 111, claimingpriority to U.S. patent application Ser. No. 14/024,961 filed Sep. 12,2013 which issued as U.S. Pat. No. 9,296,783 and is a divisionalapplication filed under 35 U.S.C. § 111, claiming priority to U.S.patent application Ser. No. 12/602,010 filed Nov. 25, 2009, which issuedas U.S. Pat. No. 8,563,000 and claims priority to United States nationalstage application filed under 35 U.S.C. § 371 of international (PCT)application no. PCT/US08/06675 filed May 23, 2008, and designating theUS, which claims priority to U.S. provisional application No. 60/931,784filed May 25, 2007.

FIELD OF THE INVENTION

The present invention relates to a series of new melanocortin receptorligands useful in treating diseases responsive to modulation of suchreceptors. The invention also relates to pharmaceutical compositionscomprising such peptide analogs and to their use in the prevention ortreatment of conditions affected by such receptors.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web, and is hereby incorporated byreference in its entirety. The ASCII copy is named “167P PCT2 SEQLISTING.txt”, created on May 20, 2008, and has the file size of 49,000bytes.

BACKGROUND OF THE INVENTION

Melanocortins are a family of regulatory peptides which are formed bypost-translational processing of pro-hormone pro-opiomelanocortin (POMC;131 amino acids in length). POMC is processed into three classes ofhormones; the melanocortins, including but not limited to α-MSH(melanocyte stimulating hormone), β-MSH and γ-MSH, adrenocorticotropinhormone (ACTH), various endorphins (e.g. lipotropin) (Cone, R. D. etal., Recent Prog. Horm. Res., 51:287-317 (1996); and Cone, R. D. et al.,Ann. N.Y. Acad. Sci., 31:342-63 (1993)) and their peptide fragments.Melanocortins have been found in a wide variety of normal human tissuesincluding the brain, adrenal, skin, testis, spleen, kidney, ovary, lung,thyroid, liver, colon, small intestine and pancreas (Tatro, J. B. etal., Endocrinol., 121:1900-7 (1987); Mountjoy, K. G. et al., Science,257:1248-51 (1992); Chhajlani, V. et al., FEBS Lett., 309:417-20 (1992);Gantz, I. et al., J. Biol. Chem., 268:8246-50 (1993) and Gantz, I. etal., J. Biol. Chem., 268:15174-9 (1993)).

Melanocortin peptides have been shown to exhibit a wide variety ofphysiological activities including the control of behavior and memory,affecting neurotrophic and antipyretic properties, as well as affectingthe modulation of the immune system. Aside from their well known effectson adrenal cortical functions (adrenocorticotropic hormone, ACTH) and onmelanocytes (melanocyte stimulating hormone, MSH), melanocortins havealso been shown to control the cardiovascular system, analgesia,thermoregulation and the release of other neurohumoral agents includingprolactin, luteinizing hormone and biogenic amines (De Wied, D. et al.,Methods Achiev. Exp. Pathol., 15:167-199 (1991); De Wied, D. et al.,Physiol. Rev., 62:977-1059 (1982); Guber, K. A. et al., Am. J. Physiol.257:R681-R94 (1989); Walker, J. M. et al., Science, 210:1247-9 (1980);Murphy, M. T. et al., Science, 221:192-3 (1983); Ellerkmann, E. et al.,Endocrinol., 130:133-8 (1992) and Versteeg, D. H. G. et al., Life Sci.,38:835-40 (1986)).

It has also been shown that binding sites for melanocortins aredistributed in many different tissue types including lachrymal andsubmandibular glands, pancreas, adipose, bladder, duodenum, spleen,brain and gonadal tissues as well as malignant melanoma tumors. Fivemelanocortin receptors (MC-R) have been characterized to date. Theseinclude melanocyte-specific receptor (MC1-R), corticoadrenal-specificACTH receptor (MC2-R), melacortin-3 (MC3-R), melanocortin-4 (MC4-R) andmelanocortin-5 receptor (MC5-R). All of the melanocortin receptorsrespond to the peptide hormone class of melanocyte stimulating hormones(MSH) (Cone, R. D. et al., Ann. N.Y. Acad. Sci., 680:342-63 (1993); andCone, R. D. et al., Recent Prog. Horm. Res., 51:287-318 (1996)).

MC1-R, known in the art as Melanocyte Stimulating Hormone Receptor(MSH-R), Melanotropin Receptor or Melanocortin-1 Receptor, is a 315amino acid transmembrane protein belonging to the family of G-Proteincoupled receptors. MC1-R is a receptor for both MSH and ACTH. Theactivity of MC1-R is mediated by G-proteins which activate adenylatecyclase. MC1-R receptors are found in melanocytes and corticoadrenaltissue as well as various other tissues such as adrenal gland,leukocytes, lung, lymph node, ovary, testis, pituitary, placenta, spleenand uterus. MC2-R, also called Adrenocorticotropic Hormone Receptor(ACTH-R), is a 297 amino acid transmembrane protein found in melanocytesand the corticoadrenal tissue. MC2-R mediates the corticotrophic effectof ACTH. In humans, MC3-R is a 360 amino acid transmembrane proteinfound in brain tissue; in mice and rats MC3-R is a 323 amino acidtransmembrane protein. MC4-R is a 332 amino acid transmembrane proteinwhich is also expressed in brain as well as placental and gut tissues.MC5-R is a 325 amino acid transmembrane protein expressed in theadrenals, stomach, lung and spleen and very low levels in the brain.MC5-R is also expressed in the three layers of adrenal cortex,predominantly in the aldosterone-producing zona glomerulosa cells.

The five known melanocortin receptors differ, however, in theirfunctions. For example, MC1-R is a G-protein coupled receptor thatregulates pigmentation in response to α-MSH, a potent agonist of MC1-R.Agonism of the MC1-R receptor results in stimulation of the melanocyteswhich causes eumelanin and increases the risk for cancer of the skin.Agonism of MC1-R can also have neurological effects. Stimulation ofMC2-R activity can result in carcinoma of adrenal tissue. Recentpharmacological confirmation has established that central MC4-Rreceptors are the prime mediators of the anorexic and orexigenic effectsreported for melanocortin agonists and antagonists, respectively. Theeffects of agonism of the MC3-R and MC5-R are not yet known.

There has been great interest in melanocortin (MC-R) receptors astargets for the design of novel therapeutics to treat disorders of bodyweight such as obesity and cachexia. Both genetic and pharmacologicalevidence points toward central MC4-R receptors as the principal target(Giraudo, S. Q. et al., Brain Res., 809:302-6 (1998); Farooqi, I. S. etal., N.E. J. Med., 348:1085-95 (2003); MacNeil, D. J. et al., Euro. J.Pharm., 44:141-57 (2002); MacNeil, D. J. et al., Euro. J. Pharm.,450:93-109 (2002); Kask, A. et al., NeuroReport, 10:707-11 (1999);Huszer, D. et al., Cell, 131-41 (1997); Klebig, M. L. et al., Proc.Natl. Acad. Sci., 92:4728-32 (1995); Karbon, E. et al., Abstr. 19^(th)Ann. Winter Neuropeptide Conf., (1998); Fan, W. et al., Nature,385:165-8 (1997); Seely, R. J., Nature, 390:349 (1997); Comuzzie, A. G.,Nat. Gen., 15:273-6 (1997); Chagnon, Y. C., Mol. Med., 3(10):663-73(1997); WO 97/47316 (Lee et al., 1997); and Shutter, J. R., Gen. & Dev.,11:593-602 (1997)). Stimulation of the MC-4 receptor by its endogenousligand, αMSH, produces a satiety signal. It is believed that byproviding potent MC-4 receptor agonists, appetite might be suppressedand weight loss achieved.

The current progress with receptor-selective agonists and antagonistsevidences the therapeutic potential of melanocortin receptor activation,particularly MC4-R.

Agonist, antagonist or other ligand compounds activating one or moremelanocortin receptor would be useful for treating a wide variety ofindications in a subject in need thereof or at risk thereof includingacute and chronic inflammatory diseases such as general inflammation(U.S. Pat. No. 6,613,874 (Mazur et al., 2003); and Catania, A. et al.,Pharm. Rev., 56:1-29 (2004)), inflammatory bowel disease (U.S. Pat. No.6,713,487 (Yu et al., 2004)); and Catania, A. et al., Pharm. Rev.,56:1-29 (2004)), brain inflammation (Catania, A. et al., Pharm. Rev.,56:1-29 (2004)), sepsis (U.S. Pat. No. 6,613,874 (Mazur et al., 2003);U.S. Pat. No. 6,713,487 (Yu et al., 2004); and Catania, A. et al.,Pharm. Rev., 56:1-29 (2004)) and septic shock (U.S. Pat. No. 6,613,874(Mazur et al., 2003); and Catania, A. et al., Pharm. Rev., 56:1-29(2004)), diseases with an autoimmune component such as rheumatoidarthritis (U.S. Pat. No. 6,713,487 (Yu et al., 2004); and Catania, A. etal., Pharm. Rev., 56:1-29 (2004)), gouty arthritis (Catania, A. et al.,Pharm. Rev., 56:1-29 (2004); and Getting, S. J. et al., Curr. Opin.Investig. Drugs, 2:1064-9 (2001)), and multiple sclerosis (U.S. Pat. No.6,713,487 (Yu et al., 2004)), metabolic diseases and medical conditionsaccompanied by weight gain such as obesity (U.S. Pat. No. 6,613,874(Mazur et al., 2003); U.S. Pat. No. 6,600,015 (Chen et al., 2003); Fehm,H. L. et al., J. Clin. Endo. & Metab., 86:1144-8 (2001); Hansen, M. J.et al., Brain Res., 1039:137-45 (2005); Ye, Z. et al., Peptides,26:2017-25 (2005); Farooqi, I. S. et al., N.E. J Med., 348:1085-95(2003); MacNeil, D. J. et al., Eu. J. Pharm., 44:141-57 (2002); MacNeil,D. J. et al., Euro. J. Pharm., 450:93-109 (2002); Kask, A. et al.,NeuroReport, 10:707-11 (1999); Schwartz, M. W., J. Clin. Invest.,108:963-4 (2001); Gura, T., Science, 287:1738-40 (2000); Raffin-Sanson,M. L., Euro. J. Endo., 144:207-8 (2001); and Hamilton, B. S. et al.,Obesity Res., 10:182-7 (2002)), feeding disorders (U.S. Pat. No.6,720,324 (Marzabadi et al., 2004); Fehm, H. L. et al., J. Clin. Endo. &Metab., 86:1144-8 (2001); and Pontillo, J. et al., Bioorganic & Med.Chem. Ltrs., 15:2541-6 (2005)) and Prader-Willi Syndrome (GE, Y. et al.,Brain Res., 957:42-5 (2002)), metabolic diseases and medical conditionsaccompanied by weight loss such as anorexia (U.S. Pat. No. 6,613,874(Mazur et al., 2003); and Wisse, B. R. et al., Endocrinology,142:3292-301 (2001)), bulimia (U.S. Pat. No. 6,720,324 (Marzabadi etal., 2004)), AIDS wasting (Marsilje, T. H. et al., Bioorg. Med. Chem.Lett., 14:3721-5 (2004); and Markison, S. et al., Endocrinology,146:2766-73 (2005)), cachexia (U.S. Pat. No. 6,613,874 (Mazur et al.,2003); Lechan, R. M. et al., Endocrinology, 142:3288-91 (2001); andPontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15:2541-6 (2005)),cancer cachexia (U.S. Pat. No. 6,639,123 (Van der Ploeg et al., 2003))and wasting in frail elderly (U.S. Pat. No. 6,639,123 (Van der Ploeg etal., 2003)), diabetes (U.S. Pat. No. 6,713,487 (Yu et al., 2004)) anddiabetalogical related conditions and complications of diabetes such asretinopathy (U.S. Pat. No. 6,525,019 (D'Amato, 2003), neoplasticproliferation (U.S. Pat. No. 6,713,487 (Yu et al., 2004)) such as skincancer (Sturm, R. A., Melanoma Res., 12:405-16 (2002); and Bastiens, M.T. et al., Am. J. Hum. Genet., 68:884-94 (2001)), and prostate cancer(Luscombe, C. J. et al., British J. Cancer, 85:1504-9 (2001)),reproductive or sexual medical conditions such as endometriosis (U.S.Pat. No. 6,713,487 (Yu et al., 2004)) and uterine bleeding in women(U.S. Pat. No. 6,613,874 (Mazur et al., 2003)), sexual dysfunction (U.S.Pat. No. 6,720,324 (Marzabadi et al., 2004); Van der Ploeg, L. H. T. etal., PNAS, 99:11381-6 (2002), Molinoff, P. B. et al., Ann. N.Y. Acad.Sci., 994:96-102 (2003), and Hopps, C. V. et al., B.J.U. Int'l.,92:534-8 (2003)), erectile dysfunction ((U.S. Pat. No. 6,613,874 (Mazuret al., 2003); Diamond, L. E. et al., Urology, 65:755-9 (2005);Wessells, H. et al., Int'l. J. Impotence Res., 12:S74-9 (2000);Andersson, K-E. et al., Int'l. J. Impotence Res., 14:S82-S92 (2002);Bertolini, A. et. al., Sexual Behavior: Pharmacology and Biochemistry,Raven Press, NY, p 247-57 (1975); Wessells, H. et al., Neuroscience,118:755-62 (2003); Wessells, H. et al., Urology, 56:641-6 (2000);Shadiack, A. M. et al., Soc. for Neuroscience Abst, (2003); Wessells, H.et al., J. Urology, 160:389-93 (1998); Rosen, R. C. et al., Int'l. J.Impotence Res., 16:135-42 (2004); and Wessells, H. et al., Peptides,26:1972-7 (2005)) and decreased sexual response in females (U.S. Pat.No. 6,713,487 (Yu et al., 2004); and Fourcroy, J. L., Drugs, 63:1445-57(2003)), diseases or conditions resulting from treatment or insult tothe organism such as organ transplant rejection (U.S. Pat. No. 6,713,487(Yu et al., 2004); and Catania, A. et al., Pharm. Rev., 56:1-29 (2004)),ischemia and reperfusion injury (Mioni, C. et al., Euro. J. Pharm.,477:227-34 (2003); and Catania, A. et al., Pharm. Rev., 56:1-29 (2004)),treatment of spinal cord injury and to accelerate wound healing (SharmaH. S. et al., Acta. Nerochir. Suppl., 86:399-405 (2003); Sharma H. S.,Ann. N.Y. Acad. Sci., 1053: 407-21 (2005); and U.S. Pat. No. 6,525,019(D'Amato, 2003)), as well as weight loss caused by chemotherapy,radiation therapy, temporary or permanent immobilization (Harris, R. B.et al., Physiol. Behav., 73:599-608 (2001)) or dialysis, cardiovasculardiseases or conditions such as hemorrhagic shock (Catania, A. et al.,Pharm. Rev., 56:1-29 (2004)), cardiogenic shock (U.S. Pat. No. 6,613,874(Mazur et al., 2003)), hypovolemic shock (U.S. Pat. No. 6,613,874 (Mazuret al., 2003)), cardiovascular disorders (U.S. Pat. No. 6,613,874 (Mazuret al., 2003)) and cardiac cachexia (Markison, S. et al., Endocrinology,146:2766-73 (2005)), pulmonary diseases or conditions such as acuterespiratory distress syndrome (U.S. Pat. No. 6,350,430 (Dooley et al.,2002); and Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), chronicobstructive pulmonary disease (U.S. Pat. No. 6,713,487 (Yu et al.,2004)), asthma (U.S. Pat. No. 6,713,487 (Yu et al., 2004)) and pulmonaryfibrosis, to enhance immune tolerance (Luger, T. A. et al.,Pathobiology, 67:318-21 (1999)) and to combat assaults to the immunesystem such as those associated with certain allergies (U.S. Pat. No.6,713,487 (Yu et al., 2004)) or organ transplant rejection (U.S. Pat.No. 6,713,487 (Yu et al., 2004)); and Catania, A. et al., Pharm. Rev.,56:1-29 (2004)), treatment of dermatological diseases and conditionssuch as psoriasis (U.S. Pat. No. 6,713,487 (Yu et al., 2004)), skinpigmentation depletion (U.S. Pat. No. 6,713,487 (Yu et al., 2004); andYe, Z. et al., Peptides, 26:2017-25 (2005)), acne (Hatta, N. et al., J.Invest. Dermatol., 116:564-70 (2001); and Bohm, M. et al., J. Invest.Dermatol., 118:533-9 (2002)), keloid formation (U.S. Pat. No. 6,525,019(D'Amato, 2003)) and skin cancer (Sturm, R.A., Melanoma Res., 12:405-16(2002); and Bastiens, M. T. et al., Am. J. Hum. Genet., 68:884-94(2001)), behavioral, central nervous system or neuronal conditions anddisorders such as anxiety (U.S. Pat. No. 6,720,324 (Marzabadi et al.,2003); and Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15:2541-6(2005)), depression (Chaki, S. et al., Peptides, 26:1952-64 (2005),Bednarek, M. A. et al., Expert Opinion Ther. Patents, 14:327-36 (2004);and U.S. Pat. No. 6,720,324 (Marzabadi et al., 2003)), memory and memorydysfunction (U.S. Pat. No. 6,613,874 (Mazur et al., 2003); and Voisey,J. et al., Curr. Drug Targets, 4:586-97 (2003)), modulating painperception (U.S. Pat. No. 6,613,874 (Mazur et al., 2003); Bertolini, A.et al., J. Endocrinol. Invest., 4:241-51 (1981); and Vrinten, D. et al.,J. Neuroscience, 20:8131-7 (2000)) and treating neuropathic pain(Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15:2541-6 (2005)),conditions and diseases associated with alcohol consumption, alcoholabuse and/or alcoholism (WO 05/060985 (Marsh et al., 2005); and Navarro,M. et al., Alcohol Clin. Exp. Res., 29:949-57 (2005)), and renalconditions or diseases such as the treatment of renal cachexia(Markison, S. et al., Endocrinology, 146:2766-73 (2005)) or natriuresis(U.S. Pat. No. 6,613,874 (Mazur et al., 2003)).

Ligand compounds activating one or more melanocortin receptor would beuseful for modulating a wide variety of normalizing or homeostaticactivities in a subject in need thereof including thyroxin release (U.S.Pat. No. 6,613,874 (Mazur et al., 2003)), aldosterone synthesis andrelease (U.S. Pat. No. 6,613,874 (Mazur et al., 2003)), body temperature(U.S. Pat. No. 6,613,874 (Mazur et al., 2003)), blood pressure (U.S.Pat. No. 6,613,874 (Mazur et al., 2003)), heart rate (U.S. Pat. No.6,613,874 (Mazur et al., 2003)), vascular tone (U.S. Pat. No. 6,613,874(Mazur et al., 2003)), brain blood flow (U.S. Pat. No. 6,613,874 (Mazuret al., 2003)), blood glucose levels (U.S. Pat. No. 6,613,874 (Mazur etal., 2003)), bone metabolism, bone formation or development (Dumont, L.M. et al., Peptides, 26:1929-35 (2005)), ovarian weight (U.S. Pat. No.6,613,874 (Mazur et al., 2003)), placental development (U.S. Pat. No.6,613,874 (Mazur et al., 2003)), prolactin and FSH secretion (U.S. Pat.No. 6,613,874 (Mazur et al., 2003)), intrauterine fetal growth (U.S.Pat. No. 6,613,874 (Mazur et al., 2003)), parturition (U.S. Pat. No.6,613,874 (Mazur et al., 2003)), spermatogenesis (U.S. Pat. No.6,613,874 (Mazur et al., 2003)), sebum and pheromone secretion (U.S.Pat. No. 6,613,874 (Mazur et al., 2003)), neuroprotection (U.S. Pat. No.6,639,123 (Van der Ploeg et al., 2003)) and nerve growth (U.S. Pat. No.6,613,874 (Mazur et al., 2003)) as well as modulating motivation (U.S.Pat. No. 6,613,874 (Mazur et al., 2003)), learning (U.S. Pat. No.6,613,874 (Mazur et al., 2003)) and other behaviors (U.S. Pat. No.6,613,874 (Mazur et al., 2003)).

Hydantoin (C₃H₂N₂O₂), also known as glycolyl urea or by its IUPAC nameimidazole-2,4(3H, 5H)-dione, is a crystalline, heterocyclic organiccompound which can be thought of as a cyclic “double-condensationreaction” product of glycolic acid and urea or allantoin, an oxidationproduct (C₄H₆N₄O₃) of uric acid that is the metabolic end product ofvertebrate purine oxidation. Hydantoin which has the following chemicalstructure:

and is similar to imidazolidine, the hydrogen-saturated analogue ofimidazole except that it has carbonyl groups in the 2^(nd) and 4^(th)positions in the ring. It has a molecular weight of 100.076 g/mol, isslightly soluble in water and has a melting point of 216-224° C.Hydantoin and its derivatives have antibacterial, antifungal,antiprotozoal and anthelmintic properties. Hydantoin has traditionallybeen an ingredient in anticonvulsants used in the treatment of seizuresassociated with epilepsy. It is believed that hydantoins depressabnormal neuronal discharges in the central nervous system. Phenytoin,another anticonvulsant synthesized from hydantoin, is used as a skeletalmuscle relaxant and for the treatment of severe trigeminal neuralgia.

Applicants have discovered a class of compounds that have a highaffinity for the melanocortin receptors, particularly selective for theMC-4 subtype relative to the other receptor subtype, especially the MC-5subtype. Specifically, Applicants discovered that peptides modified withhydantoin exhibited increased affinity for the MC-4 receptor subtype. Itis therefore an objective of this invention to provide chemicalcompounds that activate or antagonize the MC-4 receptor subtype. It is afurther an objective of the present invention to provide ligands for themelanocortin receptors which exhibit greater stability and selectivityfor melanocortin receptors than native melanocortin receptor ligands.Yet another objective of the invention is to provide means for theadministration of said compounds for the treatment of various ailmentsand/or conditions associated with either the over or the underproduction of melanocortin peptides.

SUMMARY OF THE INVENTION

Applicants have discovered a novel class of cyclic peptide analogsmodified with a hydantoin moiety that are ligands for the melanocortinreceptors and are selective for the MC-4 receptor subtype. One of theunique structural features of this new class is the use of unnatural orsynthetic amino acid residues in the N-terminal region. Suchsubstitutions contribute not only to the selectivity of the compound,but also the binding affinity at the targeted receptor. These newcompounds bind to the MC-4 receptor with low nanomolar affinity andexhibit a prolonged plasma half-life compared to α-MSH. Studies usingmale, Sprague-Dawley rats indicate that these new compounds effectivelysuppress food intake and induce body weight loss.

In particular, the present invention is directed to compounds accordingto formula (I), (II) or (III), and pharmaceutically acceptable salts,hydrates, solvates or prodrugs thereof, useful as modulators of one ormore melanocortin receptors. The invention also covers uses thereof,particularly as medicinal agents in the treatment of certain,identifiable diseases and/or conditions. According to a first aspect,the invention provides a compound of formula (I),pharmaceutically-acceptable salts, hydrates, solvates and/or prodrugsthereof

wherein the hydantoin moiety is formed from fusing the amino group ofX¹, i.e.,

with the amino and carboxyl groups of one of the amino acids comprisingX, i.e.,

together with a carbonyl group, i.e.,

In the shorthand used by the Applicants to identify an embodiment offormula (I), for examplecyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂.“Hydantoin(C(O)-(AA¹-AA²)” refers to the amino acids which form thehydantoin structure. In the aforementioned embodiment, “C(O)” refers tothe carbonyl group situated between the two nitrogens of theimidazolinyl heterocyclic ring. The first listed amino acid “AA¹” in thegiven example is Cys, contributes both its N-terminal amino andC-terminal carboxyl groups to form the highlighted section of thehydantoin moiety as indicated below

(the section of the hydantoin moiety not part of AA¹ has been brokenaway). In the illustrative example, AA² is D-Ala wherein its N-terminalamino comprises part of the hydantoin structure, as indicated in boldbelow,

R⁷ is methyl and R⁶ is a hydrogen.

In the preferred embodiment of the compounds according to formula (I),hereinafter referred to as Group I compounds, X is selected from thegroup consisting of —CH₂—S—S—CH₂—, —C(CH)₂—S—S—CH₂—, —CH₂—S—S—C(CH₃)₂—,—C(CH₃)₂—S—S—C(CH₃)₂—, —(CH₂)₂—S—S—CH₂—, —CH₂—S—S—(CH₂)₂—,—(CH₂)₂—S—S—(CH₂)₂—, —C(CH₃)₂—S—S—(CH₂)₂—, —(CH₂)₂—S—S—C(CH₃)₂—,—(CH₂)_(t)—C(O)—NR⁸—(CH₂)_(r)— and —(CH₂)_(r)—NR⁸—C(O)—(CH₂)_(t)—;

-   -   R¹ and R² each is, independently, H, (C₁-C₁₀)alkyl or        substituted (C₁-C₁₀)alkyl;    -   R³ is —OH or —NH₂;    -   R⁴ and R⁵ each is, independently, H, (C₁-C₁₀)alkyl or        substituted (C₁-C₁₀)alkyl;    -   X¹ is

-   -   A¹ is His, 2-Pal, 3-Pal, 4-Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Taz, 2-Thi,        3-Thi or is deleted;    -   A² is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X¹,X²,X³,X⁴,X⁵)Phe;    -   A³ is Arg, hArg, Dab, Dap, Lys or Orn;    -   A⁴ is Bal, 1-Nal, 2-Nal, (X¹,X²,X³,X⁴,X⁵)Phe or Trp;    -   R⁶ and R⁷ each is, independently for each occurrence thereof, H,        (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl,        substituted (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or        substituted aryl(C₁-C₅)alkyl provided that R⁶ and R⁷ may be        joined together to form a ring;    -   R⁸ is H, (C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl;    -   r is, independently for each occurrence thereof, 1, 2, 3, 4 or        5; and    -   t is, independently for each occurrence thereof, 1 or 2.

A preferred compound of the above formula, hereafter referred to asGroup I(A) compounds, is where X is selected from the group consistingof —CH₂—S—S—CH₂— and —(CH₂)₂—S—S—CH₂—;

-   -   r is, independently for each occurrence thereof, 1, 2, 3, 4 or        5;    -   t is, independently for each occurrence thereof, 1 or 2;    -   R¹, R², R⁴ and R⁵ each is H;    -   X¹ is selected from the group consisting of

-   -   A¹ is His or deleted;    -   A² is D-1-Nal, D-2-Nal or D-Phe;    -   A³ is Arg; and    -   A⁴ is Bal, 1-Nal, 2-Nal or Trp.

A preferred Group IA compound, hereafter referred to as a Group I(B)compound, is where

-   -   X¹ is

-   -   A² is D-Phe or D-2-Nal; and    -   A⁴ Trp;

Representative embodiments of the Group IB class of compounds, hereafterreferred to as Group I(C) compounds, are as follows:

-   cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH₂; or-   cyclo[Hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH₂;    with the compound    cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂ or a    pharmaceutically acceptable salt thereof, the most preferred of this    group.

In another aspect of the instant application, the invention is directedto a class of compounds hereafter referred to as Group I(D) compoundswherein X is selected from the group consisting of—(CH₂)_(t)—C(O)—NR⁶—(CH₂)_(r)— and —(CH₂)_(r)— NR⁶—C(O)—(CH₂)_(t)—.

-   -   r is, independently for each occurrence thereof, 1, 2, 3, 4 or        5;    -   t is, independently for each occurrence thereof, 1 or 2;    -   R¹, R², R⁴ and R⁵ each is H;    -   R³ is NH₂;    -   X¹ is selected from the group consisting of

-   -   A¹ is His or deleted;    -   A² is D-1-Nal, D-2-Nal or D-Phe;    -   A³ is Arg; and    -   A⁴ is Bal, 1-Nal, 2-Nal or Trp;        or a pharmaceutically acceptable salt thereof.

A subclass of the Group II compounds, the Group I(E) compounds are thosein which X is —(CH₂)_(t)—C(O)—NR⁶—(CH₂)_(r)—;

-   -   t is 1; and    -   r is 1;    -   X¹ is selected from the group consisting of:

-   -   A¹ is His;    -   A² is D-Phe;    -   A³ is Arg; and    -   A⁴ is Bal, 1-Nal, 2-Nal or Trp or pharmaceutically acceptable        salts thereof.

A preferred subclass of the Group IIA compounds, hereinafter referred toas Group I(F) compounds, are those compounds according to formula (I)wherein

-   -   X¹ is

and

R⁶ is a methyl, ethyl, propyl or butyl, preferably either a methyl orpropyl; or a pharmaceutically acceptable salt thereof. Specificexamples, classified as Group I(G) compounds, include:

-   cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂;-   cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂;-   cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂; or    cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂;    preferably,    cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂; or    cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂; or    pharmaceutically acceptable salts thereof.

In another subclass of Group I,

-   -   X¹ is

-   -   A² is D-2-Nal or D-Phe;    -   R⁶ is methyl, ethyl, propyl or butyl, preferably propyl; or        pharmaceutically acceptable salts thereof, which are referred to        as Group I(H) compounds which include the following Group I(I)        compounds:        cyclo[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH₂; or        cyclo[Hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH₂; or        pharmaceutically acceptable salts thereof.

In the preferred Group ID compounds, A² is D-2-Nal (Group I(J)) as foundin example, cyclo[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH₂(Group I(K)) or a pharmaceutically acceptable salt thereof.

In yet another subclass of the Group I compounds, known as the GroupI(L) compounds,

-   -   X¹ is selected from the group consisting of:

-   -   A² is D-2-Nal or D-Phe; and    -   R⁶ is methyl, ethyl, propyl or butyl, preferably a propyl;        or a pharmaceutically acceptable salt thereof. Specific examples        of the Group IH compounds, or the Group I(M) compounds are as        follows:

-   cyclo[Hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH₂;

-   cyclo[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH₂;

-   cyclo[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH₂;

-   cyclo[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH₂;

-   cyclo[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH₂; or

-   cyclo[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH₂; or a    pharmaceutically acceptable salts thereof. Even more preferred are    those wherein A² is D-2-Nal and R⁶ is a methyl, ethyl, propyl or    butyl, preferably a propyl; or a pharmaceutically acceptable salt    thereof (the Group I(N) class) which include the following Group    I(O) examples:

-   cyclo[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH₂;

-   cyclo[Hydantoin (C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH₂; or

-   cyclo[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH₂;    or a pharmaceutically acceptable salt thereof.

In another subgroup (Group I(P)) of the Group I compounds,

-   -   X¹ is selected from the group consisting of:

-   -   A² is D-2-Nal or D-Phe;    -   R⁶ is methyl, ethyl, propyl or butyl, preferably a propyl;        or a pharmaceutically acceptable salt thereof. The following        Group I(Q) compounds are preferred examples:

-   cyclo[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH₂;

-   cyclo[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH₂;

-   cyclo[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH₂; or

-   cyclo[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH₂;    or a pharmaceutically acceptable salt thereof, with those compounds    having D-2-Nal at A² and R⁶ a methyl (Group I(R)) as found in    cyclo[Hydantoin-(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH₂; and    cyclo[Hydantoin-(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH₂ (Group    I(S)) being most preferred of this subclass.

In yet another embodiment of the formula (I) compounds (the Group I(T)class),

-   -   X is —(CH₂)_(t)—C(O)—NR⁶—(CH₂)_(r)—;    -   t is 1; and    -   r is 2;    -   X¹ is

-   -   A¹ is His;    -   A² is D-Phe;    -   A³ is Arg;    -   A⁴ is Trp; and    -   R⁶ is methyl, ethyl, propyl or butyl;        or a pharmaceutically acceptable salts thereof. Specific        examples (Group I(U)) include,

-   cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂;

-   cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂; or

-   cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂,    or a pharmaceutically acceptable salt thereof, particularly    cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂ (Group    I(V)); or a pharmaceutically acceptable salt thereof.

In another subclass (Group I(W)),

-   -   X¹ is

-   -   A¹ is deleted;    -   A² is D-Phe;    -   A³ is Arg; and    -   R⁶ is methyl, ethyl, propyl or butyl;        or a pharmaceutically acceptable salt thereof with        cyclo[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH₂ (Group        I(X)), or a pharmaceutically acceptable salt thereof, being        preferred.

A pharmaceutically acceptable salt of a compound of formula (I) mayreadily be prepared by mixing together solutions of a compound offormula (I) and the desired acid or base, as appropriate. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent.

According to a first aspect, the invention provides a compound offormula (II), pharmaceutically-acceptable salts, hydrates, solvatesand/or prodrugs thereof

wherein the hydantoin moiety is formed from fusing the amino group ofX¹, i.e.,

with the following

to form the hydantoin structure as follows:

In the preferred embodiment of the compounds according to formula (II),hereinafter referred to as Group II compounds,

-   -   X¹ is

-   -   X² is

-   -   A¹ is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen;    -   A² is an L- or D-amino acid;    -   A³ is His, 2-Pal, 3-Pal, 4-Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Taz, 2-Thi        or 3-Thi;    -   A⁴ is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X¹,X²,X³,X⁴,X⁵)Phe;    -   A⁵ is Arg, hArg, Dab, Dap, Lys or Orn;    -   A⁶ is Bal, 1-Nal, 2-Nal, (X¹,X²,X³,X⁴,X⁵)Phe or Trp;    -   A⁷ is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen;    -   R¹ is H, (C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl;    -   R² and R³ each is, independently, H, (C₁-C₁₀)alkyl,        (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted        (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substituted        aryl(C₁-C₅)alkyl or R² and R³ may be fused together form a        cyclic moiety;    -   R⁴ is CO₂H or C(O)NH₂;    -   R⁵ and R⁶ each is, independently, H, (C₁-C₁₀)alkyl,        (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted        (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substituted        aryl(C₁-C₅)alkyl or R⁵ and R⁶ may be fused together form a        cyclic moiety;    -   R⁷ and R⁸ each is, independently, H, (C₁-C₁₀)alkyl,        (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted        (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substituted        aryl(C₁-C₅)alkyl; or R⁷ and R⁸ may be fused together form a        cyclic moiety;    -   R⁹ is H, (C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; and    -   n is, independently for each occurrence thereof, 1, 2, 3, 4, 5,        6 or 7; or a pharmaceutically acceptable salt thereof.

A preferred class of compounds according to formula (II), hereafterreferred to as Group II(A) examples, are those compounds wherein A² isD-Ala, Asn, Asp, Gln or Glu;

-   -   R⁵ and R⁶ each is, independently, H, (C₁-C₁₀)alkyl,        (C₁-C₁₀)heteroalkyl, substituted (C₁-C₁₀)alkyl or substituted        (C₁-C₁₀)heteroalkyl or R⁵ and R⁶ may be fused together form a        cyclic moiety; and    -   R⁷ and R⁸ each is, independently, H, (C₁-C₁₀)alkyl,        (C₁-C₁₀)heteroalkyl, substituted (C₁-C₁₀)alkyl or substituted        (C₁-C₁₀)heteroalkyl;        or a pharmaceutically acceptable salt thereof.    -   R¹, R², R³, and R⁹, each is, independently, H; and    -   R⁴ is C(O)NH₂;    -   A¹ is Cys;    -   A² is D-Ala or Glu;    -   A³ is His;    -   A⁴ is D-2-Nal or D-Phe;    -   A⁵ is Arg;    -   A⁶ is Trp; and    -   A⁷ is Cys or Pen;        or pharmaceutically acceptable salts thereof.

A preferred subclass of the Group IIA compounds (Group II(B)), are thosehaving

-   -   R¹, R², R³, and R⁹, each is, independently, H;    -   R⁴ is C(O)NH₂;    -   R⁵ and R⁶ each is, independently, H, methyl, n-propyl,        isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or        (CH₂)—NH—C(N)—NH₂; R⁷ is H;    -   R⁸ is methyl;    -   R⁹ is H;        or pharmaceutically acceptable salts thereof. Preferred Group        IIB compounds (Group II(C)) include:

-   Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;

-   Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;

-   Hydantoin(C(O)-(Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(D-Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-

-   Hydantoin(C(O)-(Aib-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Val-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Ile-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Leu-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;    or

-   Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;    or a pharmaceutically acceptable salts thereof.

Even more preferred (Group II (D)) are Group IIC compounds wherein A⁴ isD-Phe, such as found in the following examples (Group II(E)):

-   Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Hydantoin(C(O)-(Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(D-Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Aib-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Val-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Ile-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Leu-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;    or-   Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;    or a pharmaceutically acceptable salts thereof, particularly    Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂    (Group II(F)) or a pharmaceutically acceptable salt thereof.

A second preferred formula (II) subclass (Group II(G)) are thosecompounds wherein

-   -   R¹, R², R³, and R⁹, each is, independently, H; and    -   R⁴ is C(O)NH₂;    -   R⁵ and R⁶ each is, independently, H, methyl, isopropyl, isobutyl        or are fused together to form cyclohexyl or CH₂-cyclohexyl;    -   R⁷ is H;    -   R⁸ is n-propyl;    -   R⁹ is H;    -   A¹ is Cys;    -   A² is D-Ala or Glu;    -   A³ is His;    -   A⁴ is D-2-Nal or D-Phe;    -   A⁵ is Arg;    -   A⁶ is Trp; and    -   A⁷ is Cys or Pen;        or a pharmaceutically acceptable salts thereof. Examples from        the subclass, referred to as the Group II(H) compounds, include        the following:

-   Hydantoin(C(O)-(Ala-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Gly-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(A6c-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Gly-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(D-Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Leu-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Cha-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;    or

-   Hydantoin(C(O)-(Aib-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;    or pharmaceutically acceptable salts thereof. More preferred Group    III(H) compounds (hereafter Group II(I)) are those examples wherein    -   A² is D-Ala;    -   A⁴ D-Phe; and    -   A⁷ is Cys;        or pharmaceutically acceptable salts thereof. Specific compounds        from this preferred class (Group II(J)) include:

-   Hydantoin(C(O)-(A6c-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(D-Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Leu-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;

-   Hydantoin(C(O)-(Cha-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;    or

-   Hydantoin(C(O)-(Aib-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;    or pharmaceutically acceptable salts thereof.

A third preferred subclass of compounds according to formula (II) arethe Group II(K) class having the following requirements:

-   -   A¹ is Cys;    -   A² is D-Ala or Glu;    -   A³ is His;    -   A⁴ is D-2-Nal or D-Phe;    -   A⁵ is Arg;    -   A⁶ is Trp; and    -   A⁷ is Cys or Pen;    -   R¹, R², R³, R⁶, R⁷ and R⁹, each is, independently, H;    -   R⁸ is (CH₂)₃—NH—C(N)—NH₂;

provided that either R⁴ is C(O)NH₂ and R⁵ is H or R⁵ is C(O)NH₂ and R⁴is H; or pharmaceutically acceptable salts thereof. Preferred GroupII(L) compounds that fall within this subclass include:

-   Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;    or pharmaceutically acceptable salts thereof.

Even more preferred (the Group II(M) subclass) are those Compounds ofGroup II wherein A⁴ is D-Phe as found in the following preferredexamples (Group II(N)):

-   Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;    and-   Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;    or pharmaceutically acceptable salts thereof.

Yet another preferred embodiment of formula (II), known as Group II(O),is Hydantoin(C(O)-(Nle-Ala))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;or a pharmaceutically acceptable salt thereof.

A pharmaceutically acceptable salt of a compound of formula (II) mayreadily be prepared by mixing together solutions of a compound offormula (II) and the desired acid or base, as appropriate. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent.

The present invention also relates to a class of cyclic peptide analogsthat are ligands for the melanocortin receptors having a structureaccording to formula (III) as depicted below:

wherein the hydantoin moiety is formed from fusing the amino group ofone of the amino acids that make up X, i.e., “AA²”

with a second amino acid, i.e., “AA¹” making up X,

together with a carbonyl group, i.e., C(O), as follows:

In the shorthand used to identify an embodiment of formula (III), suchas cyclo[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,“Hydantoin(C(O)-(AA¹-AA²)” identifies the amino acids forming thehydantoin structure. The carbonyl group situated between the twonitrogens of the imidazolinyl heterocyclic ring is indicated as “C(O)”.“AA¹” is part of the hydantoin structure with either R² or R³ (dependingon the stereoisomerism of the example) being the side chain while theother is the hydrogen found on the α-carbon. “AA²” is the amino acidthat contributes its N-terminal to the hydantoin structure. For thegiven example,cyclo[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂, thehydantoin is formed as follows:

As for the variables of formula (III),

-   -   X is selected from the group consisting of —CH₂—S—S—CH₂—,        —C(CH₃)₂—S—S—CH₂—, —CH₂—S—S—C(CH₃)₂—, —C(CH₃)₂—S—S—C(CH₃)₂—,        —(CH₂)₂—S—S—CH₂—, —CH₂—S—S—(CH₂)₂, —(CH₂)₂—S—S—(CH₂)₂—,        —C(CH₃)₂—S—S—(CH₂)₂—, —(CH₂)₂—S—S—C(CH₃)₂—,        —(CH₂)_(t)—C(O)—NR⁸—(CH₂)_(r)— and —(CH₂)_(r)—        NR⁸—C(O)—(CH₂)_(t)—;    -   R¹ and R⁵ each is, independently, H, (C₁-C₁₀)alkyl or        substituted (C₁-C₁₀)alkyl;    -   R⁴ is —OH or —NH₂;    -   R⁶ and R⁷ each is, independently, H, (C₁-C₁₀)alkyl or        substituted (C₁-C₁₀)alkyl;    -   R² and R³ each is, independently, H, (C₁-C₁₀)alkyl,        (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted        (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substituted        aryl(C₁-C₅)alkyl or R² and R³ may be fused together to form a        ring;    -   A¹ is an L- or D-amino acid or deleted;    -   A² is His, 2-Pal, 3-Pal, 4-Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Taz, 2-Thi        or 3-Thi;    -   A³ is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X¹,X²,X³,X⁴,X⁵)Phe;    -   A⁴ is Arg, hArg, Dab, Dap, Lys or Orn;    -   A⁵ is Bal, 1-Nal, 2-Nal, (X¹,X²,X³,X⁴,X⁵)Phe or Trp;    -   r is, independently for each occurrence thereof, 1, 2, 3, 4 or        5; and    -   t is, independently for each occurrence thereof, 1 or 2;        or pharmaceutically acceptable salts thereof.

In the preferred embodiment of the compounds according to formula (III),hereinafter referred to as Group III compounds,

-   -   A¹ is Ala, D-Ala, Asn, Asp, Gln, Glu or Gly; or a        pharmaceutically acceptable salt thereof.

In another preferred embodiment (the Group III(A) subclass),

-   -   X is selected from the group consisting of —CH₂—S—S—CH₂—,        —C(CH₃)₂—S—S—CH₂— and —(CH₂)₂—S—S—CH₂—;    -   A¹ is D-Ala or Glu;    -   A² is His;    -   A³ is D-Phe;    -   A⁴ is Arg;    -   A⁵ is Trp;    -   R¹, R⁵, R⁶ and R⁷, each is, independently, H;    -   R² and R³ each is, independently, H, (C₁-C₁₀)alkyl,        (C₁-C₁₀)heteroalkyl, substituted (C₁-C₁₀)alkyl or substituted        (C₁-C₁₀)heteroalkyl or R² and R³ may be fused together form a        cyclic moiety; and    -   R⁴ is NH₂;        or a pharmaceutically acceptable salt thereof.

In an even more preferred subgroup of Group III(A) (the Group III(B)subclass), R² and R³ each is, independently, H, methyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or(CH₂)—NH—C(N)—NH₂; or a pharmaceutically acceptable salt thereof.Specific examples of Group III(B), are the Group III(C) compounds:

-   cyclo[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; or-   cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂; or    pharmaceutically acceptable salts thereof.

In another subclass of Group III, R² and R³ each is, independently, H,methyl, isopropyl, isobutyl, sec-butyl or may be fused together to forma cyclohexyl (hereafter the Group III(D) subclass); or pharmaceuticallyacceptable salts thereof, of which the following are preferred examplesthereof (Group III(E)):

-   cyclo[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂;-   cyclo[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; or-   cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂;    or pharmaceutically acceptable salts thereof.

In yet another preferred subclass of Group III, hereafter Group III(F),A¹ is Glu and R² and R³ each is, independently, H, or pharmaceuticallyacceptable salts thereof with the following compound (Group III(G))cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂; or apharmaceutically acceptable salt thereof, a preferred example thereof.

A pharmaceutically acceptable salt of a compound of formula (III) mayreadily be prepared by mixing together solutions of a compound offormula (III) and the desired acid or base, as appropriate. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent.

For the avoidance of doubt, unless otherwise indicated, the termsubstituted means substituted by one or more defined groups. In the casewhere groups may be selected from a number of alternative groups, theselected groups may be the same or different. For the avoidance ofdoubt, the term independently means that where more than one substituentis selected from a number of possible substituents, those substituentsmay be the same or different.

The pharmaceutically acceptable salts of the compounds of the inventionwhich contain a basic centre are, for example, non-toxic acid additionsalts formed with inorganic acids such as hydrochloric, hydrobromic,hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or withorgano-sulfonic acids. Examples include the HCl, HBr, HI, sulfate orbisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate,succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate,gluconate, camsylate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate salts. Compounds of theinvention can also provide pharmaceutically acceptable metal salts, inparticular non-toxic alkali and alkaline earth metal salts, with bases.Examples include the sodium, potassium, aluminum, calcium, magnesium,zinc and diethanolamine salts (Berge, S. M. et al., J. Pharm. Sci.,66:1-19 (1977); Gould, P. L., Int'l J. Pharmaceutics, 33:201-17 (1986);and Bighley, L. D. et al., Encyclo. Pharma. Tech., Marcel Dekker Inc,New York, 13:453-97 (1996).

The pharmaceutically acceptable solvates of the compounds of theinvention include the hydrates thereof. Also included within the scopeof the invention and various salts of the invention are polymorphsthereof. Hereinafter, compounds their pharmaceutically acceptable salts,their solvates or polymorphs, defined in any aspect of the invention(except intermediate compounds in chemical processes) are referred to as“compounds of the invention”.

The compounds of the invention may possess one or more chiral centersand so exist in a number of stereoisomeric forms. All stereoisomers andmixtures thereof are included in the scope of the present invention.Racemic compounds may either be separated using preparative HPLC and acolumn with a chiral stationary phase or resolved to yield individualenantiomers utilizing methods known to those skilled in the art. Inaddition, chiral intermediate compounds may be resolved and used toprepare chiral compounds of the invention.

The compounds of the invention may exist in one or more tautomericforms. All tautomers and mixtures thereof are included in the scope ofthe present invention. For example, a claim to 2-hydroxypyridinyl wouldalso cover its tautomeric form, α-pyridonyl.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)(which hereinafter will include formulae I(A) to I(X)), formula (II)(which hereinafter will include formulae II(A) to II(P)), or formula(III), (which hereinafter will include formulae III(A) to IIII(G)), orpharmaceutically acceptable salts thereof together with apharmaceutically acceptable carrier or diluent.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, whereinsaid compound is a melanocortin receptor agonist or antagonist.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, whereinsaid compound is a selective melanocortin-4 receptor agonist.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, whereinsaid compound is a selective melanocortin-4 receptor agonist with afunctional activity characterized by an EC₅₀ at least 15-fold moreselective for the human melanocortin-4 receptor than for the humanmelanocortin-1 receptor, the human melanocortin-3 receptor and the humanmelanocortin-5 receptor.

In yet another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, whereinsaid compound is a selective melanocortin-4 receptor agonist with afunctional activity characterized by an EC₅₀ at least 17-fold moreselective for the human melanocortin-4 receptor than for the humanmelanocortin-3 receptor, an EC₅₀ at least 90-fold more selective for thehuman melanocortin-4 receptor than for the human melanocortin-3receptor, an EC₅₀ at least 200-fold more selective for the humanmelanocortin-4 receptor than for the human melanocortin-5 receptor, oran EC₅₀ at least 3000-fold more selective for the human melanocortin-4receptor than for the human melanocortin-5 receptor.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating an acute or chronic inflammatory disease or medicalcondition such as general inflammation, inflammatory bowel disease,brain inflammation, sepsis and septic shock.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a disease or medical condition with an autoimmune componentsuch as rheumatoid arthritis, gouty arthritis and multiple sclerosis.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a metabolic disease or medical condition accompanied byweight gain such as obesity, feeding disorders and Prader-WilliSyndrome. In a further aspect, the disease or condition treated isobesity. In yet a further aspect, the disease or condition treated is afeeding disorder.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor decreasing food intake, for decreasing body weight, or a combinationthereof.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor decreasing food intake without compromising body weight. In yetanother aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor decreasing food consumption while increasing body weight.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a metabolic disease or medical condition accompanied byweight loss such as anorexia, bulimia, AIDS wasting, cachexia, cancercachexia and wasting in frail elderly.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor increasing food intake, for increasing body weight, or a combinationthereof.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a neoplastic disease or medical condition such as skincancer and cancer cachexia.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a reproductive or sexual medical condition such asendometriosis, uterine bleeding, sexual dysfunction, erectiledysfunction and decreased sexual response in females.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a disease or medical condition resulting from treatment orinsult to an organism such as organ transplant rejection, ischemia andreperfusion injury, wounding and spinal cord injury, and weight loss dueto a medical procedure selected from the group consisting ofchemotherapy, radiation therapy, temporary or permanent immobilizationand dialysis.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a cardiovascular disease or medical condition such ashemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovasculardisorders and cardiac cachexia.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a pulmonary disease or medical condition such as acuterespiratory distress syndrome, pulmonary fibrosis, chronic obstructivepulmonary disease and asthma.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor enhancing immune tolerance and treating allergies.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a dermatological disease or medical condition such aspsoriasis, skin pigmentation depletion, acne and keloid formation.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a behavioral or central nervous system or neuronal diseaseor medical condition such as anxiety, depression, memory dysfunction andneuropathic pain.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor treating a renal disease or medical condition such as renal cachexiaand natriuresis.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor modulating ovarian weight, placental development, prolactinsecretion, FSH secretion, intrauterine fetal growth, parturition,spermatogenesis, thyroxin release, aldosterone synthesis and release,body temperature, blood pressure, heart rate, vascular tone, brain bloodflow, blood glucose levels, sebum secretion, pheromone secretion,motivation, learning and behavior, pain perception, neuroprotection andnerve growth.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor modulating bone metabolism, bone formation and bone development.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent, usefulfor inhibiting alcohol consumption, for reducing alcohol consumption,for treating alcoholism, or for overcoming alcohol abuse. In a furtheraspect, the compound of the composition useful for inhibiting alcoholconsumption, for reducing alcohol consumption, for treating alcoholism,or for treating alcohol abuse is a selective melanocortin-4 receptoragonist. In yet a further aspect, the compound of the composition usefulfor inhibiting alcohol consumption is a selective melanocortin-4receptor agonist, or a pharmaceutically acceptable salt thereof, with afunctional activity characterized by an EC₅₀ at least 15-fold moreselective for the human melanocortin-4 receptor than for the humanmelanocortin-1 receptor, the human melanocortin-3 receptor and the humanmelanocortin-5 receptor. In yet another aspect, the compound of thecomposition useful for inhibiting alcohol consumption is a selectivemelanocortin-4 receptor agonist, or a pharmaceutically acceptable saltthereof, with a functional activity characterized by an EC₅₀ at least17-fold more selective for the human melanocortin-4 receptor than forthe human melanocortin-3 receptor, an EC₅₀ at least 90-fold moreselective for the human melanocortin-4 receptor than for the humanmelanocortin-3 receptor, an EC₅₀ at least 200-fold more selective forthe human melanocortin-4 receptor than for the human melanocortin-5receptor, or an EC₅₀ at least 3000-fold more selective for the humanmelanocortin-4 receptor than for the human melanocortin-5 receptor.

In another aspect, the present invention provides the use of atherapeutically effective amount of a melanocortin-4 receptor agonistcompound of formula (I), formula (II) or formula (III), or apharmaceutically acceptable salt thereof, for the manufacture of amedicament useful for inhibiting alcohol consumption, for reducingalcohol consumption, for treating alcoholism, or for treating alcoholabuse in a subject in need of such treatment.

In yet another aspect, the present invention provides a method ofeliciting an agonist or an antagonist effect from a melanocortinreceptor in a subject in need thereof which comprises administering tosaid subject an effective amount of a compound of formula (I), formula(II) or formula (III), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of elicitingan agonist or an antagonist effect from a melanocortin receptor in asubject in need thereof which comprises administering to said subject aneffective amount of a compound of formula (I), formula (II) or formula(III), or a pharmaceutically acceptable salt thereof, wherein saidcompound is a selective melanocortin-4 receptor agonist.

In another aspect, the present invention provides a method of elicitingan agonist or an antagonist effect from a melanocortin receptor in asubject in need thereof which comprises administering to said subject aneffective amount of a compound of formula (I), formula (II) or formula(III), or a pharmaceutically acceptable salt thereof, wherein saidcompound is a selective melanocortin-4 receptor agonist with afunctional activity characterized by an EC₅₀ at least 15-fold moreselective for the human melanocortin-4 receptor than for the humanmelanocortin-1 receptor, the human melanocortin-3 receptor and the humanmelanocortin-5 receptor.

In yet another aspect, the present invention provides a method ofeliciting an agonist or an antagonist effect from a melanocortinreceptor in a subject in need thereof which comprises administering tosaid subject an effective amount of a compound of formula (I), formula(II) or formula (III), or a pharmaceutically acceptable salt thereof,wherein said compound is a selective melanocortin-4 receptor agonistwith a functional activity characterized by an EC₅₀ at least 17-foldmore selective for the human melanocortin-4 receptor than for the humanmelanocortin-3 receptor, an EC₅₀ at least 90-fold more selective for thehuman melanocortin-4 receptor than for the human melanocortin-3receptor, an EC₅₀ at least 200-fold more selective for the humanmelanocortin-4 receptor than for the human melanocortin-5 receptor, oran EC₅₀ at least 3000-fold more selective for the human melanocortin-4receptor than for the human melanocortin-5 receptor.

In another aspect, the present invention provides a method of treatingan acute or chronic inflammatory disease or medical condition such asgeneral inflammation, inflammatory bowel disease, brain inflammation,sepsis and septic shock by eliciting an agonist or antagonist effectfrom a melanocortin receptor by administering an effective amount of acompound of formula (I), formula (II) or formula (III), or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating adisease or medical condition with an autoimmune component such asrheumatoid arthritis, gouty arthritis and multiple sclerosis byeliciting an agonist or antagonist effect from a melanocortin receptorby administering an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides a method of treating ametabolic disease or medical condition accompanied by weight gain suchas obesity, feeding disorders and Prader-Willi Syndrome by eliciting anagonist or antagonist effect from a melanocortin receptor byadministering an effective amount of a compound of formula (I), formula(II) or formula (III), or a pharmaceutically acceptable salt thereof. Ina further aspect of the foregoing method, the disease or conditiontreated is obesity. In yet a further aspect of the foregoing method, thedisease or condition treated is a feeding disorder.

In another aspect, the present invention provides a method of decreasingfood intake, decreasing body weight, or a combination thereof, byeliciting an agonist or antagonist effect from a melanocortin receptorby administering an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof.

In another, the present invention provides a method of decreasing foodintake without compromising body weight by eliciting an agonist orantagonist effect from a melanocortin receptor by administering aneffective amount of a compound of formula (I), formula (II) or formula(III), or a pharmaceutically acceptable salt thereof. In yet anotheraspect of the foregoing method, the present invention provides a methodof decreasing food intake while increasing body weight by eliciting anagonist or antagonist effect from a melanocortin receptor byadministering an effective amount of a compound of formula (I), formula(II) or formula (III), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of increasingfood intake, increasing body weight or a combination thereof, byeliciting an agonist or antagonist effect from a melanocortin receptorby administering an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides a method of treating ametabolic disease or medical condition accompanied by weight loss suchas anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia andwasting in frail elderly by eliciting an agonist or antagonist effectfrom a melanocortin receptor by administering an effective amount of acompound of formula (I), formula (II) or formula (III), or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating aneoplastic disease or medical condition such as skin cancer and cancercachexia by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I), formula (II) or formula (III), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method of treating areproductive or sexual medical condition such as endometriosis, uterinebleeding, sexual dysfunction, erectile dysfunction and decreased sexualresponse in females by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I), formula (II) or formula (III), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method of treating adisease or medical condition resulting from treatment or insult to anorganism such as organ transplant rejection, ischemia and reperfusioninjury, wounding and spinal cord injury, and weight loss due to amedical procedure selected from the group consisting of chemotherapy,radiation therapy, temporary or permanent immobilization and dialysis byeliciting an agonist or antagonist effect from a melanocortin receptorby administering an effective amount of a compound of formula (I),formula (II) or formula (III), or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides a method of treating acardiovascular disease or medical condition such as hemorrhagic shock,cardiogenic shock, hypovolemic shock, cardiovascular disorders andcardiac cachexia by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I), formula (II) or formula (III), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method of treating apulmonary disease or medical condition such as acute respiratorydistress syndrome, pulmonary fibrosis, chronic obstructive pulmonarydisease and asthma by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I), formula (II) or formula (III), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method of enhancingimmune tolerance or treating allergies by eliciting an agonist orantagonist effect from a melanocortin receptor by administering aneffective amount of a compound of formula (I), formula (II) or formula(III), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treatingdermatological disease or medical condition such as psoriasis, skinpigmentation depletion, acne and keloid formation by eliciting anagonist or antagonist effect from a melanocortin receptor byadministering an effective amount of a compound of formula (I), formula(II) or formula (III), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating abehavioral or central nervous system or neuronal disease or medicalcondition such as anxiety, depression, memory dysfunction andneuropathic pain by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I), formula (II) or formula (III), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method of treating arenal disease or medical condition such as renal cachexia andnatriuresis by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I), formula (II) or formula (III), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method of modulatinga normalizing or homeostatic activity such as ovarian weight, placentaldevelopment, prolactin secretion, FSH secretion, intrauterine fetalgrowth, parturition, spermatogenesis, thyroxin release, aldosteronesynthesis and release, body temperature, blood pressure, heart rate,vascular tone, brain blood flow, blood glucose levels, sebum secretion,pheromone secretion, motivation, learning and behavior, pain perception,neuroprotection and nerve growth by eliciting an agonist or antagonisteffect from a melanocortin receptor by administering an effective amountof a compound of formula (I), formula (II) or formula (III), or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of modulatinga normalizing or homeostatic activity such as bone metabolism, boneformation and bone development by eliciting an agonist or antagonisteffect from a melanocortin receptor by administering an effective amountof a compound of formula (I), formula (II) or formula (III), or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of inhibitingalcohol consumption, for reducing alcohol consumption, for treatingalcoholism, or for treating alcohol abuse by eliciting an agonist orantagonist effect from a melanocortin receptor by administering aneffective amount of a compound of formula (I), formula (II) or formula(III), or a pharmaceutically acceptable salt thereof. In a furtheraspect of the foregoing method, the compound is a selectivemelanocortin-4 receptor agonist. In yet a further aspect of theimmediately foregoing method, the compound of the composition useful forinhibiting alcohol consumption is a selective melanocortin-4 receptoragonist, or a pharmaceutically acceptable salt thereof, with afunctional activity characterized by an EC₅₀ at least 15-fold moreselective for the human melanocortin-4 receptor than for the humanmelanocortin-1 receptor, the human melanocortin-3 receptor and the humanmelanocortin-5 receptor. In yet another aspect of the foregoing method,the compound of the composition useful for inhibiting alcoholconsumption is a selective melanocortin-4 receptor agonist, or apharmaceutically acceptable salt thereof, with a functional activitycharacterized by an EC₅₀ at least 17-fold more selective for the humanmelanocortin-4 receptor than for the human melanocortin-3 receptor, anEC₅₀ at least 90-fold more selective for the human melanocortin-4receptor than for the human melanocortin-3 receptor, an EC₅₀ at least200-fold more selective for the human melanocortin-4 receptor than forthe human melanocortin-5 receptor, or an EC₅₀ at least 3000-fold moreselective for the human melanocortin-4 receptor than for the humanmelanocortin-5 receptor.

In a further aspect, the present invention provides the use of atherapeutically effective amount of a melanocortin-4 receptor agonist orantagonist compound according to formula (I), formula (II) or formula(III), or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament useful to treat a disease and/or medicalcondition selected from the group consisting of acute and chronicinflammatory diseases such as general inflammation, inflammatory boweldisease, brain inflammation, sepsis and septic shock; diseases with anautoimmune component such as rheumatoid arthritis, gouty arthritis andmultiple sclerosis; metabolic diseases and medical disorders accompaniedby weight gain such as obesity, feeding disorders and Prader-WilliSyndrome; metabolic diseases and medical disorders accompanied by weightloss such as anorexia, bulimia, AIDS wasting, cachexia, cancer cachexiaand wasting in frail elderly; diabetes, diabetalogical relatedconditions and complications of diabetes such as retinopathy; neoplasticproliferation such as skin cancer and prostate cancer; reproductive orsexual medical conditions such as endometriosis and uterine bleeding inwomen, sexual dysfunction, erectile dysfunction and decreased sexualresponse in females; diseases or conditions resulting from treatment orinsult to the organism such as organ transplant rejection, ischemia andreperfusion injury, spinal cord injury and wounding, as well as weightloss caused chemotherapy, radiation therapy, temporary or permanentimmobilization or dialysis; cardiovascular diseases or conditions suchas hemorrhagic shock, cardiogenic shock, hypovolemic shock,cardiovascular disorders and cardiac cachexia; pulmonary diseases orconditions such as acute respiratory distress syndrome, chronicobstructive pulmonary disease, asthma and pulmonary fibrosis; to enhanceimmune tolerance and to combat assaults to the immune system such asthose associated with certain allergies or organ transplant rejection;treatment of dermatological diseases and conditions such as psoriasis,skin pigmentation depletion, acne, keloid formation and skin cancer;behavioral, central nervous system and neuronal disorders such asanxiety, depression, memory dysfunction, and neuropathic pain; and renalconditions or diseases such as the treatment of renal cachexia andnatriuresis.

In a further aspect, the present invention provides the use of atherapeutically effective amount of a melanocortin-4 receptor agonist orantagonist compound according to formula (I), formula (II) or formula(III), or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament useful to modulate normalizing orhomeostatic activities such as ovarian weight, placental development,prolactin secretion, FSH secretion, intrauterine fetal growth,parturition, spermatogenesis, thyroxin release, aldosterone synthesisand release, body temperature, blood pressure, heart rate, vasculartone, brain blood flow, blood glucose levels, sebum secretion, pheromonesecretion, motivation, learning and behavior, pain perception,neuroprotection, nerve growth, bone metabolism, bone formation and bonedevelopment.

It will be appreciated that therapeutic interventions addressing bothnormal physiological and pathophysiological processes which utilize themelanocortin receptors are also contemplated.

Additional objects, advantages, and features of the present inventionwill become apparent from the following description and appended claims,taken in conjunction with the accompanying figures.

The compounds of formula (I), formula (II) and formula (III) are ligandsfor at least one of the melanocortin receptors (MC1-R, MC2-R, MC3-R,MC4-R and MC5-R), preferably MC4-R, and a selection thereof were testedfor their ability to act as a ligand in the in vitro assay describedbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Cumulative mean food intake difference from vehicle in rats at 1hour and 4 hours after administration of various concentrations ofCompound A.

FIG. 2A. Cumulative mean food intake difference from vehicle in ratsafter administration of various concentrations of Compounds C and D.

FIG. 2B. Cumulative mean food intake difference from vehicle in ratsafter administration of various concentrations of Compounds A, B, C, D,E and F.

FIG. 3A. Cumulative mean food intake difference from vehicle in ratsafter administration of 4.5 mole/Kg/day of Compound A.

FIG. 3B. Cumulative mean body weight difference from vehicle in ratsafter administration of 4.5 mole/Kg/day of Compound A.

FIG. 4A. Cumulative mean food intake difference from vehicle in ratsafter administration of 300 ηmole/Kg/day of Compounds A, C and D.

FIG. 4B. Cumulative mean body weight difference from vehicle in ratsafter administration of 300 ηmole/Kg/day of Compounds A, C and D.

LEGEND for FIG. 1 to FIG. 4B:

Letter Code Compound Formula Acyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp- Dap]-NH₂ BHydantoin(C(O)-(D-Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg- Trp-Cys)-NH₂ CHydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp- Cys)-NH₂ DHydantoin(C(O)-(Gly-D-Arg))-c(Cys-Glu-His-D-Phe-Arg- Trp-Cys)-NH₂ EHydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp- Cys)-NH₂ FHydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp- Cys)-NH₂

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms,Abbreviations and Acronyms

The following are definitions of terms used in this specification. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the present specification, individually or aspart of another group, unless otherwise indicated. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs.

The term “alkyl” refers to straight or branched chain hydrocarbon groupshaving 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkylgroups, that is, alkyl groups of 1 to 4 carbon atoms, are mostpreferred. When a subscript is used with reference to an alkyl or othergroup, the subscript refers to the number of carbon atoms that the groupmay contain.

The term “substituted alkyl” refers to an alkyl group as defined abovehaving one, two or three substituents selected from the group consistingof halo, amino, cyano, keto (═O), —OR_(a), —SR_(a), NR_(a)R_(b), —(C═O)R_(a), —CO₂R_(a), —C(═O)NR_(a)R_(b), —NR_(a)C(═O)R_(b), NR_(a)CO₂R_(b),—OC(═O)R_(a), —OC(═O)NR_(a)R_(b), —NR_(c)C(═O)NR_(a)R_(b),NR_(a)SO₂R_(d), SO₂R_(d), SO₃R_(d), cycloalkyl, aryl, heteroaryl, orheterocycle, wherein the groups R_(a), R_(b), and R_(c) are selectedfrom hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, heterocycle, cycloalkyl,or (C₁-C₆)alkyl substituted with halogen, hydroxy, methoxy, nitro,amino, cyano, —(C═O)H, —CO₂H, —(C═O)alkyl, —CO₂alkyl, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, carboxy, acyl, —C(═O)H, —C(═O)phenyl,—CO₂-alkyl, cycloalkyl, —(C═O)NH₂, —(C═O)NH(alkyl),—(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —C(═O)—(CH₂)₁₋₂NH₂,—C(═O)—(CH₂)₁₋₂NH(alkyl), —C(═O)—(CH₂)₁₋₂N(alkyl)₂, —NH—CH₂-carboxy,—NH—CH₂—CO₂-alkyl, phenyl, benzyl, phenylethyl, or phenyloxy. The groupR_(d) may be selected from the same groups as R_(a), R_(b) and R_(c) butis not hydrogen. Alternatively, the groups R_(a) and R_(b) may togetherform a heterocyclo or heteroaryl ring. It should be understood that whena substituted alkyl group is substituted with an aryl, cycloalkyl,heteroaryl, or heterocyclo, such rings are as defined below and thus mayhave one to three substituents as set forth below in the definitions forthese terms.

When the term “alkyl” is used as a suffix following another specificallynamed group, e.g., arylalkyl or heteroarylalkyl, the term defines, withmore specificity, at least one of the substituents that the substitutedalkyl will contain.

For example, arylalkyl refers to an aryl bonded through an alkyl, or inother words, a substituted alkyl group having from 1 to 12 carbon atomsand at least one substituent that is aryl (e.g., benzyl or biphenyl).“Lower arylalkyl” refers to substituted alkyl groups having 1 to 4carbon atoms and at least one aryl substituent.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms and at least one double bond. Alkenylgroups of 2 to 6 carbon atoms and having one double bond are mostpreferred.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms and at least one triple bond. Alkynylgroups of 2 to 6 carbon atoms and having one triple bond are mostpreferred. A substituted alkenyl or alkynyl will contain one, two, orthree substituents as defined above for alkyl groups.

The term “alkylene” refers to bivalent straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms, e.g., {—CH₂—}_(n), wherein n is 1 to 12, preferably 1 to 8. Loweralkylene groups, that is, alkylene groups of 1 to 4 carbon atoms, aremost preferred. The terms “alkenylene” and “alkynylene” refer tobivalent radicals of alkenyl and alkynyl groups, respectively, asdefined above. Substituted alkylene, alkenylene, and alkynylene groupsmay have substituents as defined above for substituted alkyl groups.

The term “alkoxy” refers to the group ORe wherein Re is alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, heterocycle, or cycloalkyl. Thus, an alkoxy includes suchgroups as methoxy, ethoxy, cyclopropyloxy, pyrrolidinyloxy, and soforth. The term “aryloxy” refers to the groups O(aryl) or O(heteroaryl),wherein aryl and heteroaryl are as defined below.

The term “alkylthio” refers to an alkyl or substituted alkyl group asdefined above bonded through one or more sulfur (—S—) atoms, e.g.,—S(alkyl) or —S(alkyl-R_(a)).

The term “alkylamino” refers to an alkyl or substituted alkyl group asdefined above bonded through one or more nitrogen (—NR_(f)—) groups,wherein R_(f) is hydrogen, alkyl, substituted alkyl, or cycloalkyl.

The term “acyl” refers to an alkyl or substituted alkyl group as definedabove bonded through one or more carbonyl {—C(═O)—} groups. When theterm acyl is used in conjunction with another group, as in acylamino,this refers to the carbonyl group {—C(═O)} linked to the second namedgroup. Thus, acylamino refers to —C(═O)NH₂, substituted acylamino refersto the group —C(═O)NRR, and acylaryl refers to —C(═O)(aryl).

The term “aminoacyl” refers to the group —NR_(f)C(═O)R_(g), whereinR_(g) is hydrogen, alkyl, or substituted alkyl, and R_(f) is as definedabove for alkylamino groups.

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.Unless otherwise indicated, any haloalkyl, haloalkoxy or haloalkylthiogroup contains one or more halo atoms which halo atoms may be the sameor different.

The term “carboxy” when used alone refers to the group CO₂H.Carboxyalkyl refers to the group CO₂R, wherein R is alkyl or substitutedalkyl.

The term “sulphonyl” refers to a sulphoxide group (i.e., —S(O)₁₋₂—)linked to an organic radical including an alkyl, alkenyl, alkynyl,substituted alkyl, substituted alkenyl, or substituted alkynyl group, asdefined above. The organic radical to which the sulphoxide group isattached may be monovalent (e.g., —SO₂-alkyl), or bivalent (e.g.,—SO₂-alkylene, etc.) The term “cycloalkyl” refers to substituted andunsubstituted monocyclic or bicyclic hydrocarbon groups of 3 to 9 carbonatoms which are, respectively, fully saturated or partially unsaturated,including a fused aryl ring, for example, an indan. A cycloalkyl groupmay be substituted by one or more (such as one to three) substituentsselected from alkyl, substituted alkyl, aminoalkyl, halogen, cyano,nitro, trifluoromethyl, hydroxy, alkoxy, alkylamino, sulphonyl,—SO₂(aryl), —CO₂H, —CO₂-alkyl, —C(═O)H, keto, —C(═O)—(CH₂)₁₋₂NH₂,—C(═O)—(CH₂)₁₋₂NH(alkyl), —C(═O)—(CH₂)₁₋₂N(alkyl)₂, acyl, aryl,heterocycle, heteroaryl, or another cycloalkyl ring of 3 to 7 carbonatoms. The term “cycloalkylene” refers to a cycloalkyl forming a link orspacer between two other groups, i.e., a cycloalkylene is a cycloalkylthat is bonded to at least two other groups. The term cycloalkylincludes saturated or partially unsaturated carbocyclic rings having acarbon-carbon bridge of three to four carbon atoms or having a benzenering joined thereto. When the cycloalkyl group is substituted with afurther ring, said further ring may have one to two substituentsselected from R_(k), wherein R_(k) is lower alkyl, hydroxy, loweralkoxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro,and lower alkyl substituted with one to two hydroxy, lower alkoxy,amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, and/or nitro.

The term “aryl” refers to substituted and unsubstituted phenyl,1-naphthyl and 2-naphthyl, with phenyl being preferred. The aryl mayhave zero, one, two or three substituents selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, alkylthio, halo,hydroxy, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy,sulphonyl, —SO₂(aryl), —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy,acyl, —C(═O)H, —C(═O)phenyl, —CO₂-alkyl, cycloalkyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂-carboxy,—NH—CH₂—CO₂-alkyl, —C(═O)—(CH₂)₁₋₂NH₂, —C(═O)—(CH₂)₁₋₂NH(alkyl),—C(═O)—(CH₂)₁₋₂N(alkyl)₂, phenyl, benzyl, phenylethyl, phenyloxy,phenylthio, heterocyclo, heteroaryl, or a (C₃-C₇)cycloalkyl ring. Theterm “arylene” refers to an aryl as defined above forming a link orspacer between two other groups, i.e., an arylene is an aryl that isbonded to at least two other groups. When the aryl group is substitutedwith a further ring, said further ring may have one to two substituentsselected from R_(k), wherein R_(k) is defined as above.

The term “heterocyclo” or “heterocycle” refers to substituted andunsubstituted non-aromatic 3- to 7-membered monocyclic groups, 7- to11-membered bicyclic groups, and 10- to 15-membered tricyclic groupswhich have at least one heteroatom (O, S or N) in at least one of therings. Each ring of the heterocyclo group containing a heteroatom cancontain one or two oxygen or sulfur atoms and/or from one to fournitrogen atoms provided that the total number of heteroatoms in eachring is four or less, and further provided that the ring contains atleast one carbon atom. The fused rings completing the bicyclic andtricyclic groups may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The nitrogen and sulfur atoms mayoptionally be oxidized and the nitrogen atoms may optionally bequaternized. The heterocyclo group may be attached at any availablenitrogen or carbon atom. The heterocyclo ring may contain one, two orthree substituents selected from the group consisting of halo, amino,cyano, alkyl, substituted alkyl, trifluoromethyl, trifluoromethoxy,sulphonyl, —SO₂(aryl), —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, alkoxy,alkylthio, hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy,phenylthio, carboxy, —CO₂-alkyl, cycloalkyl, —C(═O)H, acyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂-carboxy,—NH—CH₂—CO₂-alkyl, —C(═O)—(CH₂)₁₋₂NH₂, —C(═O) —(CH₂)₁₋₂NH(alkyl),—C(═O)—(CH₂)₁₋₂N(alkyl)₂, heterocyclo, heteroaryl, a (C₃-C₇)cycloalkylring, keto, ═N—OH, ═N—O-lower alkyl, or a five or six-membered ketal,i.e., 1,3-dioxolane or 1,3-dioxane. When the heterocyclo group issubstituted with a further ring, said further ring may have one to twosubstituents selected from R_(k), wherein R_(k) is defined as above.Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl,imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups,and 11- to 14-membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings. Each ring of theheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less and each ringhas at least one carbon atom. The fused rings completing the bicyclicand tricyclic groups may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The nitrogen and sulfur atoms mayoptionally be oxidized and the nitrogen atoms may optionally bequaternized. Heteroaryl groups which are bicyclic or tricyclic mustinclude at least one fully aromatic ring but the other fused ring orrings may be aromatic or non-aromatic. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring. Theheteroaryl ring system may contain one, two or three substituentsselected from the group consisting of halo, amino, cyano, alkyl,substituted alkyl, trifluoromethyl, trifluoromethoxy, sulphonyl,—SO₂(aryl), —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, alkoxy, alkylthio,hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,carboxy, —CO₂-alkyl, cycloalkyl, —C(═O)H, acyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂-carboxy,—NH—CH₂—CO₂-alkyl, —C(═O)—(CH₂)₁₋₂NH₂, —C(═O)—(CH₂)₁₋₂NH(alkyl),—C(═O)—(CH₂)₁₋₂N(alkyl)₂, heterocyclo, heteroaryl, or a(C₃-C₇)cycloalkyl ring. The heterocyclo ring may have a sulfurheteroatom that is substituted with one or more oxygen (═O) atoms.Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like. Exemplary bicyclicheteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl,benzoxaxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl,indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl,tetrahydroquinolinyl and the like. Exemplary tricyclic heteroaryl groupsinclude carbazolyl, benzidolyl, phenanthrollinyl, acridinyl,phenanthridinyl, xanthenyl and the like.

When reference is made herein to a particularly-named heterocyclic orheteroaryl group, such as azetidinyl, imidazolyl, piperazinyl, and soforth, the named ring may optionally contain one or more (preferably oneto three) substituents selected from the substituents recited above forheteroaryl and heterocyclo groups, as appropriate.

When reference is made to a particularly-named group having at least oneheterocyclo, heteroaryl, or carbocyclic ring “joined” thereto, it ismeant that two substituents attached to the same, adjacent, ornon-adjacent atoms of the particularly-named group may join to form asecond or third ring (i.e., the further ring may be fused, bridged orattached in a spiro fashion). Each ring of these bicyclic or tricyclicgroups may be optionally substituted, wherein the substituents areselected from those recited above for cycloalkyl, aryl, heterocyclo andheteroaryl groups. Thus, an imidazole having at least one ring joinedthereto may include an aryl-fused imidazole such as benzimidazole havingone or more (preferably one to three substituents), to anheteroaryl-fused imidazole such as a pyridoimidazole having one or more(preferably one to three) substituents, and so forth.

Additionally, one skilled in the field may make appropriatesubstitutions for the various groups of compounds of formula (I), (II)or (III) herein without departing from the spirit and scope of theinvention. Throughout the specification, groups and substituents thereofmay be chosen to provide stable moieties and compounds.

The compounds of formula (I), (II) or (III) form salts which are alsowithin the scope of this invention. Reference to a compound of any oneof formula (I), (II) or (III) herein is understood to include referenceto salts thereof, unless otherwise indicated. The term “salt(s)”, asemployed herein, denotes acidic and/or basic salts formed with inorganicand/or organic acids and bases. In addition, when a compound of any oneof formula (I), (II) or (III) contains both a basic moiety, such as butnot limited to an amine or a pyridine or imidazole ring, and an acidicmoiety, such as but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare also contemplated as within the scope of the invention, e.g., theymay be useful in isolation or purification steps which may be employedduring preparation. Salts of the compounds of any one of formula (I),(II) or (III) may be formed, for example, by reacting a compound offormula (I), (II) or (III) with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

The compounds of any one of formula (I), (II) or (III) which contain abasic moiety, such as, but not limited to an amine or a pyridine orimidazole ring, may form salts with a variety of organic and inorganicacids. Exemplary acid addition salts include acetates (such as thoseformed with acetic acid or trihaloacetic acid, for example,trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of any one of formula (I), (II) or (III) which contain anacidic moiety, such as, but not limited to a carboxylic acid, may formsalts with a variety of organic and inorganic bases. Exemplary basicsalts include ammonium salts, alkali metal salts such as sodium,lithium, and potassium salts, alkaline earth metal salts such as calciumand magnesium salts, salts with organic bases (for example, organicamines) such as benzathines, dicyclohexylamines, hydrabamines [formedwith N,N-bis(dehydro-abietyl)ethylenediamine], N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like.

Basic nitrogen-containing groups may be quaternized with agents such aslower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g., benzyl and phenethyl bromides), and others.

Prodrugs and solvates of the compounds of this invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of anyone of formula (I), (II) or (III), and/or a salt and/or solvate thereof.Solvates of the compounds of formula (I), (II) or (III) are preferablyhydrates.

Compounds of any one of formula (I), (II) or (III) and salts thereof mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers of the present compounds, such as those, for example,which may exist due to asymmetric carbons, including enantiomeric forms(which may exist even in the absence of asymmetric carbons) anddiastereomeric forms, are contemplated and within the scope of thisinvention. Individual stereoisomers of the compounds of this inventionmay, for example, be substantially free of other isomers, or may beadmixed, for example, as racemates or with all other or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations.

The terms “polypeptide,” “peptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues. Theterms apply to amino acid polymers in which one or more amino acidresidue is an artificial chemical mimetic of a corresponding naturallyoccurring amino acid, as well as to naturally occurring amino acidpolymers and non-naturally occurring amino acid polymers. Thenomenclature used to define the peptides is that typically used in theart wherein the amino group at the N-terminus appears to the left andthe carboxyl group at the C-terminus appears to the right.

The term “amino acid” refers to naturally occurring and synthetic aminoacids, as well as amino acid analogs and amino acid mimetics thatfunction in a manner similar to the naturally occurring amino acids.Unless otherwise indicated, with the exception of the N-terminal aminoacid, all abbreviations (e.g. Ala) of amino acids in this disclosurestand for the structure of —NH—C(R)(R′)—CO—, wherein R and R′ each is,independently, hydrogen or the side chain of an amino acid (e.g., R═CH₃and R′═H for Ala), or R and R′ may be joined to form a ring system. Forthe N-terminal amino acid, the abbreviation stands for the structure of:

Naturally occurring amino acids are those encoded by the genetic code,as well as those amino acids that are later modified. The term “aminoacid analog” refers to a compound that has the same basic chemicalstructure as a naturally occurring amino acid, i.e., an α-carbon that isbound to a hydrogen, a carboxyl group, an amino group, and an R group,e.g., homoserine and norleucine. Such analogs have modified R groups(e.g., norleucine) or modified peptide backbones, but retain the samebasic chemical structure as a naturally occurring amino acid. “Aminoacid mimetics” refers to chemical compounds that have a structure thatis different from the general chemical structure of an amino acid, butthat functions in a manner similar to a naturally occurring amino acid.

Amino acids may be referred to herein by either their commonly knownthree letter symbols or by the one-letter symbols recommended by theIUPAC-IUB Biochemical Nomenclature Commission.

Nomenclature and Abbreviations

Symbol Meaning Abu α-aminobutyric acid Acc 1-amino-1-cyclo(C₃—C₉)alkylcarboxylic acid such as: A3c 1-amino-1-cyclopropanecarboxylic acid A4c1-amino-1-cyclobutanecarboxylic acid A5c1-amino-1-cyclopentanecarboxylic acid A6c1-amino-1-cyclohexanecarboxylic acid Aha 7-aminoheptanoic acid Ahx6-aminohexanoic acid Aib α-aminoisobutyric acid Aic2-aminoindan-2-carboxylic acid Ala or A alanine β-Ala beta-alanine Apcdenotes the structure:

Apn 5-aminopentanoic acid (HN—(CH₂)₄—C(O)) Arg or R arginine hArghomoarginine Asn or N asparagine Asp or D aspartic acid Bal3-benzothienylalanine Bip 4,4′-biphenylalanine, represented by thestructure

Bpa 4-benzoylphenylalanine 4-Br-Phe 4-bromo-phenylalanine Chaβ-cyclohexylalanine hCha homo-cyclohexylalanine Chg cyclohexylglycineCys or C cysteine hCys homocysteine Dab 2,4-diaminobutyric acid Dap2,3-diaminopropionic acid Dip β,β-diphenylalanine Doc8-amino-3,6-dioxaoctanoic acid with the structure of:

2-Fua β-(2-fury1)-alanine Gaba 4-aminobutyric acid Gln or Q glutamineGlu or E glutamic acid Gly or G glycine His or H histidine 3-Hyptrans-3-hydroxy-L-proline, i.e., (2S, 3S)-3-hydroxypyrrolidine-2-carboxylic acid 4-Hyp 4-hydroxyproline, i.e., (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid Ile or I isoleucine Leu or Lleucine hLeu homoleucine Lys or K lysine Met or M methionine β-hMetβ-homomethionine 1-Nal β-(1-naphthyl)alanine: 2-Nalβ-(2-naphthyl)alanine Nip nipecotic acid Nle norleucine Oicoctahydroindole-2-carboxylic acid Orn ornithine 2-Palβ-(2-pyridyl)alanine 3-Pal β-(3-pyridyl)alanine 4-Palβ-(4-pyridyl)alanine Pen penicillamine Phe or F phenylalanine hPhehomophenylalanine Pro or P proline hPro homoproline Ser or S serine Tletert-Leucine Taz β-(4-thiazolyl)alanine 2-Thi β-(2-thienyl)alanine 3-Thiβ-(3-thienyl)alanine Thr or T threonine Trp or W tryptophan Tyr or Ytyrosine D-(Et)Tyr has a structure of

Val or V valine

The letter “D” preceding the above three-letter abbreviations, e.g. asin “D-Nal” or “D-Phe”, denotes the D-form of the amino acid. The letter“L” preceding an amino acid three-letter abbreviation denotes thenatural L-form of the amino acid. For purposes of this disclosure,unless otherwise indicated, absence of a “D” or “L” designationindicates that the abbreviation refers to the L-form. Where the commonsingle-letter abbreviation is used, capitalization refers to the L-formand small letter designation refers to the D-form, unless otherwiseindicated.

The designation “NH₂” in e.g.,Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂, indicates that theC-terminus of the peptide is amidated.Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys), or alternativelyAc-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH, indicates that theC-terminus is the free acid.

“-c(Cys-Cys)-” or “-cyclo(Cys-Cys)-” denotes the structure:

“-c(Cys-Pen)-” or “-cyclo(Cys-Pen)-” denotes the structure:

“-c(Asp-Lys)-” or “-cyclo(Asp-Lys)-” denotes the structure:

Applicants have devised the following shorthand used in naming thespecific embodiments and/or species:

“HydantoinC(O)-(A^(a)-A^(b))” denotes the structure:

wherein amino acid “A^(a)” has the structure:

andamino acid “A^(b)” the structure:

For example, a compound represented as“cyclo[Hydantoin(C(O)-(Cys-A^(b)))-A¹-A²-A³-A⁴-Cys]-” would have thefollowing the structure:

whereas a compound represented as“cyclo[Hydantoin(C(O)-(A^(b)-Cys))-A¹-A²-A³-A⁴-Cys]-” would have thestructure:

For further guidance,“cyclo[Hydantoin(C(O)-(Asp-A^(b)))-A¹-A²-A³-A⁴-Lys]-” represents thefollowing compound:

whereas “cyclo[Hydantoin(C(O)-(Dap-A^(b)))-A¹-A²-A³-A⁴-Asp]-” has thefollowing formula:

As used herein, “MC-3 agonist”, “MC-4 agonist” “MC-5 agonist” refers toa compound with affinity for the MC-3 receptor, MC-4 receptor or MC-5receptor, respectively, that results in measurable biological activityin cells, tissues, or organisms which contain the MC-3, MC-4 or MC-5receptor. Assays which demonstrate MC-3/MC-4/MC-5 agonistic activity ofcompounds are well known in the art.

As used herein, “MC-3 antagonist”, “MC-4 antagonist” and “MC-5antagonist” refer to compounds with affinity for the MC-3 receptor, MC-4receptor or MC-5 receptor, respectively, and blocks stimulation by aknown MC agonist. Assays used to determine MC-3/MC-4/MC-5 antagonisticactivity of a compound are known by one skilled in the art.

As used herein, “MC-3 receptor”, “MC-4 receptor” and “MC-5 receptor”mean the known MC-3, MC-4 and MC-5 receptors, their splice variants, andun-described receptors. MC-3 receptors are described by Gantz et al.,supra (human MC-3); Desarnaud et al., supra (mouse MC-3); and Reyfuss,L. et al., “Identification of a Receptor for Gamma Melanotropin andOther Proopiomelanocortin Peptides in the Hypothalamus and LimbicSystem”, Proc. Natl. Acad. Sci. USA, 90:8856-60 (1993). MC-4 receptorsare described by Gantz et al., supra (human MC-4); Alvaro, J. D. et al.,“Morphine Down-Regulates Melanocortin-4 Receptor Expression in BrainRegions that Mediate Opiate Addiction”, Mol-Pharmacol., 50(3):583-91(1996); and Takeuchi, S. et al., “Melanocortin Receptor Genes in theChicken-Tissue Distributions”, Gen-Comp-Endocrinol., 112(2):220-31(1998)

As used herein, “measurable” means the biologic effect is bothreproducible and significantly different from the baseline variabilityof the assay.

A “pharmaceutically-acceptable salt” is a cationic salt formed at anyacidic (carboxylic acid) group, or an anionic salt formed at any basic(e.g., amino) group and are known in the art, as described in WO87/05297 (Johnston et al., 1987), incorporated by reference herein.Preferred cationic salts include the alkali metal salts (such as sodiumand potassium), and alkaline earth metal salts (such as magnesium andcalcium) and organic salts. Preferred anionic salts include the halides(such as chloride salts), sulfonates, carboxylates, phosphates, and thelike. Clearly contemplated in such salts are addition salts that mayprovide an optical center where once there is none. For example, achiral tartrate salt may be prepared from the compounds of theinvention, and this definition includes such chiral salts. The skilledartisan is able to prepare any number of salts given the knowledge inthe art. Furthermore, the skilled artisan may prefer one salt to anotherfor reasons of solubility, stability, formulation ease and the like.Determination and optimization of such salts is within the purview ofthe skilled artisan's practice.

The phrase “specifically (or selectively) binds” to melanocortinreceptor when referring to a protein or peptide, refers to a bindingreaction that is determinative of the presence of the protein in aheterogeneous population of proteins and other biologics. Thus, underdesignated immunoassay conditions, the specified peptides bind to aparticular melanocortin receptor at a greater rate than the backgroundand do not substantially bind in a significant amount to other proteinspresent in the sample. Typically, a specific or selective reaction willbe at least twice background signal or noise and more typically morethan 10 to 100 times background.

As used herein, “selective” means having an activation preference for aspecific receptor over other receptors which can be quantified basedupon whole cell, tissue, or organism assays which demonstrate receptoractivity, such as the cAMP enzyme immunoassay (EIA) system. A compound'sselectivity is determined from a comparison of its EC₅₀ values at therelevant receptors being referenced. As used herein, use of the term“selective over the other MC receptors” means selective with respect toall other MC-R receptors. For example, a compound having an EC₅₀ of 8 nMat the MC-4 receptor and an EC₅₀ of ≥80 nM at the MC-1, MC-2, MC-3 andMC-5 receptors has a selectivity ratio for the MC-4 receptor over theother MC receptors of at least 1:10. Additionally, it will be recognizedthat selectivity may also refer to one of the MC-1, MC-2 or MC-5receptors individually. For example, a compound having an EC₅₀ of 8 nMat the MC-4 receptor and an EC₅₀ of 80 nM at the MC-1 receptor has aselectivity ratio for the MC-4 receptor over the MC-1 receptor of 1:10.Such a compound is selective over the MC-1 receptor, regardless of itsEC₅₀ value for MC-2 or MC-5.

As used herein, the terms “treat”, “treating” and “treatment” includepalliative, curative and prophylactic treatment.

Methods of Preparation

The peptides of this invention can be prepared by standard solid phasepeptide synthesis. See, e.g., Stewart, J. M., et al., Solid PhaseSynthesis, (Pierce Chemical Co., 2d ed. 1984). Starting materials arecommercially available or can be readily prepared by one of ordinaryskill in the art using known methods. Solvents, temperatures, pressuresand other reaction conditions may readily be selected by one of ordinaryskill in the art.

The substituents R² and R³ of the above generic formula may be attachedto the free amine of the N-terminal amino acid by standard methods knownin the art. For example, alkyl groups, e.g., (C₁-C₃₀)alkyl, may beattached using reductive alkylation. Hydroxyalkyl groups, e.g.,(C₁-C₃₀)hydroxyalkyl, may also be attached using reductive alkylationwherein the free hydroxy group is protected with a t-butyl ester. Acylgroups, e.g., COE¹, may be attached by coupling the free acid, e.g.,E¹COOH, to the free amine of the N-terminal amino acid by mixing thecompleted resin with 3 molar equivalents of both the free acid anddiisopropylcarbodiimide in methylene chloride for one hour. If the freeacid contains a free hydroxy group, e.g., p-hydroxyphenylpropionic acid,then the coupling should be performed with an additional 3 molarequivalents of HOBT.

When R¹ is —NH₂, the synthesis of the peptide starts with an Fmoc-aminoacid which is coupled to the Rink Amide MBHA resin. If R¹ is —OH, thesynthesis of the peptide starts with a Fmoc-amino acid which is coupledto Wang resin.

In the synthesis of a peptide of this invention containing A6c and/orAib, the coupling time is 2 hours for these residues and the residueimmediately following them.

The indicated steps may be varied to increase yield of desired product.The skilled artisan will recognize the judicious choice of reactants,solvents, and temperatures is an important component in any successfulsynthesis. Determination of optimal conditions is routine, thus theskilled artisan can make a variety of compounds using the guidance ofthe below descriptions.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out standard manipulations of organiccompounds without further direction; that is, it is well within thescope and practice of the skilled artisan to carry out suchmanipulations. These include, but are not limited to, reduction ofcarbonyl compounds to their corresponding alcohols, oxidations ofhydroxyls and the like, acylations, aromatic substitutions bothelectrophilic and nucleophilic, etherification, esterification andsaponification and the like.

The skilled artisan will also readily appreciate that certain reactionsare best carried out when potentially reactive functionalities on themolecule are masked or protected, thus avoiding any undesirable sidereactions and/or increasing the yield of the reaction. It is recognizedthat it is preferable to use a protecting group for any reactivefunctionality such as a carboxyl, hydroxyl and the like. This isstandard practice, well within the normal practice of the skilledartisan. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan.

Certain abbreviations used during the description of the synthesis ofthe representative examples that follow are defined as follows:

-   -   Ac: acyl group, i.e. CH₃C(═O)—    -   Boc: tert-butyloxycarbonyl    -   Bzl: benzyl    -   DCM: dichloromethane    -   DIC: N, N-diisopropylcarbodiimide    -   DIPEA: diisopropylethyl amine    -   Dmab:        4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl)-amino}        benzyl    -   DMAP: 4-(dimethylamino)pyridine    -   DMF dimethylformamide    -   DNP: 2,4-dinitrophenyl    -   DTT: dithiothrietol    -   Fm: fluorenylmethyl    -   Fmoc: fluorenylmethyloxycarbonyl    -   For: formyl    -   HATU:        O-(7-azabenzothiazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate    -   HBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   cHex: cyclohexyl    -   HOAT: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HOBT: 1-hydroxy-benzotriazole hydrate    -   MBHA: 4-methylbenzhydrylamine    -   Mmt: 4-methoxytrityl    -   Mtt: N-e-4-methyltrityl    -   NMP: N-methylpyrrolidone    -   ODmab:        4{N-[1-(4,4-dimethyl-2,6-dioxo-cyclohexylidene)-3-methylbutyl]-amino}benzyloxy    -   O-tBu: oxy-tert-butyl    -   Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl    -   PyAoP:        7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium-hexafluorophosphate    -   PyBroP: bromo-tris-pyrrolidino-phosphonium hexafluorophosphate    -   tBu: tert-butyl    -   TIS: triisopropylsilane    -   TOS: tosyl    -   Trt: trityl    -   TFA: trifluoroacetic acid    -   TFFH: tramethylfluoroforamidinium hexafluorophosphate    -   Z: benzyloxycarbonyl

Representative examples for synthesizing representative compounds of thepresent invention are disclosed in Examples 1-5. The described methodsfor making a peptide of this invention employ methods that arewell-known to those skilled in the art. Other methods are also known tothose skilled in the art. The examples are provided for the purpose ofillustration and are not meant to limit the scope of the presentinvention in any manner.

Example 1: cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂

The hydantoin containing, cyclic peptide amide,cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂ wasassembled using Fmoc-chemistry on an Apex peptide synthesizer (AAPPTEC;Louisville, Ky., USA). To begin, 135 mg of 0.78 mmol/g (0.105 mmoles)Rink Amide MBHA resin (Novabiochem; San Diego, Calif., USA) was placedin a reaction well and pre-swollen in 1.5 mL of dimethylformamide (DMF)prior to synthesis. Cycle 1: The resin was treated with two 1.5 mLportions of 25% piperidine in DMF for 5 minutes and 25 minutesrespectively, followed by 4 washes of 1.5 mL DMF; each wash consistingof adding 1.5 mL of solvent, mixing for 1 minute and then emptying for 1minute. Amino acids stocks were prepared in N-methylpyrrollidinone (NMP)as 0.45 M solutions containing 0.45M N-hydroxybenzotriazole (HOBT).Diisopropylcarbodiimde (DIC) was prepared as a 1.3 M solution in NMP. Tothe de-blocked resin was added 1.45 mL (0.7 mmoles) of the first aminoacid, Fmoc-cysteine(Trt)-OH (Novabiochem; San Diego, Calif., USA), alongwith 0.5 mL (0.65 mmoles) of DIC. After one hour of constant mixing thereagents were drained from the resin and the coupling step repeated.Following amino acid acylation, the resin was washed with two 1.5 mLaliquots of DMF; each washing lasting 1 minute in duration. The processof assembling the peptide (deblock/wash/acylate/wash) was repeated forcycles 2-7 which were conducted with the identical procedure describedfor cycle 1. In particular, the following amino acids were used, Cycle2: Fmoc-Trp(Boc)-OH (Genzyme; Cambridge, Mass., USA); Cycle 3:Fmoc-Arg(Pbf)-OH (Novabiochem; San Diego, Calif., USA); Cycle 4:Fmoc-D-Phe-OH (Genzyme; Cambridge, Mass., USA); Cycle 5:Fmoc-His(Trt)-OH (Novabiochem; San Diego, Calif., USA); Cycle 6:Fmoc-D-Ala-OH (Genzyme; Cambridge, Mass., USA); and Cycle 7:Fmoc-Cys(Trt)-OH, (Novabiochem; San Diego, Calif., USA). The N-terminalFmoc was removed with 25% piperidine in DMF which was followed by four1.5 mL DMF washes lasting 1 minute per washing.

The peptide-resin was conditioned with several milliliters of1,4-dioxane/water (9:1), drained, and then treated with 5.6 mL (80 eq)of 1.5M diisopropylethyl amine (DIPEA) in dioxane/water (9:1) followedby 1 mL of 0.32 M (3.0 eq) of phenylchloroformate in dioxane/water(9:1). The solution was mixed for 1 hour, drained and washed withdioxane/water several times followed by ethyl ether several times. Theresin was then treated with 0.5 M DIPEA in DMF and mixed for two hours.The resin was again washed with dioxane/water followed by an ethylether.

To the resulting peptide-resin, 5 mL of the following reagent was added:2% triisopropylsilane (TIS), 5% water, 5% (w/v) dithiothrieitol (DTT),88% trifluoroacetic acid (TFA); and the mixture was allowed to blend for3.5 hours. The filtrate that formed was collected into 40 mL of coldanhydrous ethyl ether. The precipitate was pelleted for 10 minutes at3500 RPM in a refrigerated centrifuge. The ether was decanted and thepeptide re-suspended in fresh ether. The ether workup was performed atotal of 3 times. Following the last ether wash, the peptide was allowedto air dry to remove any residual ether.

The peptide was dissolved in 10% acetonitrile and analyzed by massspectrometry and reverse-phase HPLC employing a 30×4.6 cm C₁₈ column(Vydac; Hesperia, Calif., USA) with a gradient of 2-60% acetonitrile(0.1% TFA) over 30 minutes. This analysis identified a product with >42%purity with the remainder being primarily the non-hydantoin containingproduct. Mass analysis employing electrospray ionization identified amain product containing a mass of 947.42 da which corresponds to thedesired reduced product. The crude product (˜95 mg) was diluted to aconcentration of 2 mg/mL in 5% acetic acid. To this solution 0.5 Miodine/methanol was added drop wise with vigorous stirring until a paleyellow color was achieved. The solution was vigorously stirred foranother 10 minutes. Excess iodine was then quenched by adding 1.0 Msodium thiosulfate under continuous mixing until the mixture wasrendered colorless. The peptide was re-examined by mass spectrometryanalysis and HPLC. Mass spectrometry analysis identified a main specieswith a mass of 944.44, suggesting successful oxidation of the peptide.The peptide solution was concentrated to ˜10 mL using a centrifugalevaporator and then purified on a preparative HPLC equipped with a C₁₈column using a similar elution gradient. The purified product wasre-analyzed by HPLC for purity (>95%) and mass spectrometry (945.1 da)and subsequently lyophilized. Following lyophillization 13.6 mg ofpurified product was obtained representing a 13.7% yield.

Example 2: cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂

The hydantoin-containing, peptide lactamcyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂ wasassembled using Fmoc-chemistry on an Apex peptide synthesizer (AAPPTEC;Louisville, Ky., USA). To start, 135 mg of 0.78 mmol/g (0.105 mmoles)Rink Amide MBHA resin (Novabiochem; San Diego, Calif., USA) was placedin a reaction well and pre-swollen in 1.5 mL of dimethylformamide (DMF).Cycle 1: The resin was treated with two 1.5 mL portions of 25%piperidine in DMF for 5 and 10 minutes, respectively, followed by 4washes of 1.5 mL DMF; each wash consisting of adding 1.5 mL of solvent,mixing for 1 minute then emptying for 1 minute. Amino acids stocks wereprepared in N-methylpyrrollidinone (NMP) as 0.45 M solutions containing0.45 M N-hydroxybenzotriazole (HOBT). Diisopropylcarbodiimide (DIC) wasprepared as a 1.3 M solution in NMP. To the de-blocked resin, 1.45 mL ofthe first amino acid (0.62 mmoles), i.e., Fmoc-Dap(Mtt)-OH (Novabiochem;San Diego, Calif., USA), was added together with 0.5 mL (0.62 mmoles) ofDIC. After one hour of constant mixing, the reagents were drained offand the coupling step repeated. Following amino acid acylation, theresin was washed with two 1.5 mL aliquots of DMF for 1 minute per wash.The process of assembling the peptide (deblock/wash/acylate/wash) wasrepeated for cycles 2-7 which were identical to cycle 1, as describedabove. The following amino acids were used, respectively for the cyclesas indicated: Cycle 2: Fmoc-trp(Boc)-OH (Genzyme; Cambridge, Mass.,USA); Cycle 3: Fmoc-Arg(Pbf)-OH (Genzyme; Cambridge, Mass., USA); Cycle4: Fmoc-D-Phe-OH (Novabiochem; San Diego, Calif., USA): Cycle 5:Fmoc-His(Trt)-OH (Genzyme; Cambridge, Mass., USA); Cycle 6:Fmoc-D-Ala-OH, (Genzyme; Cambridge, Mass., USA); and Cycle 7:Fmoc-Glu(O-2-PhiPr)-OH (Bachem, King of Prussia, Pa.). The N-terminalFmoc was removed with 25% piperidine in DMF followed by four, 1 minutewashings with 1.5 mL DMF then three, 1 minute washings withdichloromethane (DCM).

The resin was conditioned with 80 eq of 1.5 M diisopropylethylamine(DIPEA) in DCM followed by 2.0 eq of p-nitrophenylchloroformate in DCM.The solution was mixed for 2 hours, drained and washed with DMF severaltimes. The resin was then treated with 10 eq of DIPEA in DMF and mixedfor 30 minutes. The resin was washed with DMF and thereafter with DCM.

The Mtt (methyltrityl) side-chain protecting group of diaminopropionicacid (Dap) as well as the O-2-PhiPr (O-2-phenylisopropyl) side-chainprotecting group of glutamic acid (Glu) were both removed after 10washes of 5 mL of 5% triisopropylsilane (TIS) and 1% trifluoroaceticacid (TFA) in DCM for 3-5 minutes each. Following the last wash, theresin was again washed first with DCM and then twice with DMF. The resinwas treated twice with DIPEA (10 eq) in DMF for 2 minute treatmentsfollowed by 4 washes with DMF. An aliquot of resin (<1 mg) gave apositive Kaiser test (positive control: dark blue color). The resin wasthen treated with the 10 eq 0.5 M HOBT, 10 eq of 0.5 M PyAop, 20 eq of 2M DIPEA and 0.5 eq of 0.45 M DMAP for 8 hours with constant stirring. Afollow-up Kaiser test was slightly positive indicating incomplete lactamformation. A second round of lactam forming conditions was employedusing 10 eq of 0.5 M HOAT, 2 eq of 0.5 M HATU, 20 eq of 1 M DIPEA, and0.5 eq of 0.45 M DMAP with constant stirring for 4 hours. A follow-upKaiser test was negative (no visible blue color) for the presence of afree amine. The resin was washed once with DMF then three times withDCM.

Approximately 5 mL of the following reagent was added to the resin: 2%TIS, 5% water, 5% (w/v) dithiothrieitol (DTT) and 88% TFA; which wasallowed to mix for 3.5 hours. The filtrate was collected into 40 mL ofcold anhydrous ethyl ether. The precipitate was pelleted for 10 minutesat 3500 RPM in a refrigerated centrifuge. The ether was decanted and thepeptide re-suspended in fresh ether. The ether workup was performed atotal of 3 times. Following the last ether wash, the peptide was allowedto air dry to remove residual ether. The resulting peptide was dissolvedin 10% acetonitrile and analyzed by mass spectrometry. A single productwith a mass of 938.7 da was identified, corresponding to the desiredhydantoin-lactam peptide-product. The crude product (˜90 mg) waspurified on a preparative HPLC equipped with a Cis column using asuitable elution gradient. The purified product was re-analyzed by HPLCfor purity (>95%) and lyophilized resulting in 24 mg of product obtainedrepresenting a yield of 25%.

Example 3:cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂

The hydantoin containing cyclic peptide amidecyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂ wasassembled using Fmoc-chemistry on an Apex peptide synthesizer (AAPPTEC,Louisville, Ky., USA). Prior to the commencement of the synthesis, 220mg of 0.91 mmol/g (0.20 mmoles) Rink Amide MBHA resin (PolymerLaboratories, Amherst, Mass., USA) was placed in a reaction well andpre-swollen in 3.0 mL of dimethylformamide (DMF). Cycle 1: The resin wastreated with two 3 mL portions of 25% piperidine in DMF for 5 and 10minutes intervals, respectively, which were followed by 4 washes of 3 mLDMF; each wash consisting of introducing 3 mL of solvent, mixing for 1minute and emptying for 1 minute. Amino acids stocks were prepared inN-methylpyrrollidinone (NMP) as 0.45 M solutions containing 0.45 MN-hydroxybenzotriazole (HOBT). HBTU[2-(1H-benzo-triazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] was prepared as a 0.45 M solution in NMP anddiisopropylethylamine (DIPEA) was prepared as a 2.73 M solution in NMP.To the de-blocked resin, 2 mL of the first amino acid (0.9 mmoles),Fmoc-Cys(Trt)-OH (Novabiochem; San Diego, Calif., USA) was added alongwith 2 mL (0.9 mmoles) of HBTU and 1.5 mL (4.1 mmoles) of DIPEA. Afterone hour of constant mixing, the reagents were drained off and thecoupling step repeated. Following amino acid acylation, the resin washwashed with two 3 mL aliquots of DMF for 1 minute intervals. The processof assembling the peptide (deblock/wash/acylate/wash) was repeated forcycles 2-8 which were identical cycle 1 as described above. Thefollowing amino acids were used: Cycle 2: Fmoc-Trp(Boc)-OH (Genzyme;Cambridge, Mass., USA); Cycle 3: Fmoc-Arg(Pbf)-OH (Novabiochem; SanDiego, Calif., USA); Cycle 4: Fmoc-D-Phe-OH (Genzyme; Cambridge, Mass.,USA); Cycle 5: Fmoc-His(Trt)-OH (Novabiochem; San Diego, Calif., USA);Cycle 6: Fmoc-Glu-OH (Genzyme; Cambridge, Mass., USA); Cycle 7:Fmoc-Cys(Trt)-OH, (Novabiochem; San Diego, Calif., USA); and Cycle 8:Fmoc-Gly-OH (Novabiochem; San Diego, Calif., USA). The N-terminal Fmocwas removed with 25% piperidine in DMF as discussed previously followedby four, 1 minute washes of 3 mL DMF.

The resin was conditioned with 80 eq of 1.5M DIPEA in dichloromethane(DCM) followed by the addition of 1.1 eq of p-nitrophenylchloroformatein DCM. The solution was mixed for 2 hours, drained and washed with DMFseveral times. The resin was then treated with 10 eq of DIPEA in DMF andmixed for 30 minutes. The resin was again washed with DMF followed by aDCM wash.

To the resin, 5 mL of the following reagent was added and allowed to mixfor 3½ hours: 2% triisopropylsilane (TIS), 5% water, 5% (w/v)dithiothrieitol (DTT) and 88% trifluoroacetic acid (TFA). The filtratethat formed was collected into 40 mL of cold anhydrous ethyl ether. Theprecipitate was pelleted for 10 minutes at 3500 RPM in a refrigeratedcentrifuge. The ether was decanted and the collected peptide wasre-suspended in fresh ether. The ether workup was performed 3 times.Following the last ether wash, the peptide was air dried to removeresidual ether.

The dried peptide was dissolved in 10% acetonitrile and analyzed by massspectrometry and reverse-phase HPLC analysis using a 30×4.6 cm C₁₈column (Vydac; Hesperia, Calif., USA) with a gradient of 2-60%acetonitrile (0.1% TFA) for a period of 30 minutes. The HPLC analysisidentified a product that was 30% pure. The non-hydantoin containingproduct accounted for the remaining percentage. Mass analysis employingelectrospray ionization identified a main product containing a mass of1062 da corresponding to the desired reduced product. The crude product(˜200 mg) was diluted to a concentration of 2 mg/mL in 5% acetic acid.To this solution, 0.5 M iodine/methanol was added drop-wise withvigorous stirring until a pale yellow color was achieved. The solutionwas vigorously stirred for another 10 minutes. Excess iodine was thenquenched by adding 1.0 M sodium thiosulfate under continuous mixinguntil the mixture was rendered colorless. The peptide was re-examined bymass spectrometry analysis and HPLC. Mass spectrometry analysisidentified a main species with mass of 1060.4 da suggesting successfuloxidation of the peptide. The peptide solution was concentrated to ˜10mL using a centrifugal evaporator and then purified on a preparativeHPLC equipped with a C₁₈ column using a similar elution gradient. Thepurified product was re-analyzed by HPLC for purity (>95%) and massspectrometry (1059.7 da) and subsequently lyophilized. Followinglyophillization, 16.8 mg of purified product was collected; a 7.9%yield.

Example 4:Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂

The hydantoin containing, cyclic peptide amide,Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂,was assembled using Fmoc-chemistry on an Apex peptide synthesizer(APAPPTEC; Louisville, Ky., USA). Prior to the commencement of thesynthesis of the titled compound, 220 mg of 0.91 mmol/g (0.20 mmoles)Rink Amide MBHA resin (Polymer Laboratories, Amherst, Mass., USA) wasplaced in a reaction well to pre-swell in 3.0 mL of dimethylformamide(DMF). Cycle 1: The resin was treated with two 3 mL portions of 25%piperidine in DMF for 5 and 10 minutes intervals, respectively, whichwere followed by 4 washes of 3 mL DMF; each wash consisting of the stepsof adding 3 mL of solvent, mixing for 1 minute and then emptying for 1minute. Amino acids stocks were prepared in N-methylpyrrollidinone (NMP)as 0.45 M solutions containing 0.45 M N-hydroxybenzotriazole (HOBT).HBTU [2-(1H-benzo-triazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] was prepared as a 0.45 M solution in NMP.Diisopropylethylamine (DIPEA) was prepared as a 2.73 M solution in NMP.To the de-blocked resin, 2 mL of the first amino acid (0.9 mmoles),i.e., Fmoc-Cys(Trt)-OH (Novabiochem; San Diego, Calif., USA) was addedalong with 2 mL (0.9 mmoles) of HBTU and 1.5 mL (4.1 mmoles) of DIPEA.After one hour of constant mixing, the reagents were drained off and thecoupling step repeated. Following the amino acid acylation process, theresin wash washed with two 3 mL aliquots of DMF for 1 minute periods.The peptide assembly process, i.e., de-blocking, washing, acylating andwashing as described above for cycle 1, was repeated for cycles 2-9. Ineach particular cycle, the following amino acids were used, asindicated: Cycle 2: Fmoc-Trp(Boc)-OH (Genzyme; Cambridge, Mass., USA);Cycle 3: Fmoc-Arg(Pbf)-OH (Novabiochem; San Diego, Calif., USA); Cycle4: Fmoc-D-Phe-OH (Genzyme; Cambridge, Mass., USA); Cycle 5:Fmoc-His(Trt)-OH (Novabiochem; San Diego, Calif., USA); Cycle 6:Fmoc-Glu-OH (Genzyme; Cambridge, Mass., USA); Cycle 7: Fmoc-Cys(Trt)-OH,(Novabiochem; San Diego, Calif., USA); Cycle 8: Fmoc-D-Arg(Pbf)-OH(Genzyme; Cambridge, Mass., USA); and Cycle 9: Fmoc-Gly-OH (Novabiochem;San Diego, Calif., USA). The N-terminal Fmoc protecting group wasremoved with a solution of 25% piperidine in DMF, as previous described,followed by four 3 mL DMF washes lasting 1 minute each.

The resin was conditioned with 80 eq of 1.5 M DIPEA in dichloromethane(DCM) followed by the addition of 1.1 eq of p-nitrophenylchloroformatein DCM. The reaction was mixed for 2 hours, the solvent was drained offand the resulting product was washed with DMF several times. The resinwas treated with 10 eq of DIPEA in DMF and mixed for approximately 30minutes. The resin was washed with DMF followed by DCM.

To the resin, 5 mL of the following reagent was added: 2%triisopropylsilane (TIS), 5% water, 5% (w/v) dithiothreitol (DTT) and88% trifluoroacetic acid (TFA). The solution was mixed for 3.5 hours.The filtrate was collected into 40 mL of cold anhydrous ethyl ether. Theprecipitate was pelleted for 10 minutes at 3500 RPM in a refrigeratedcentrifuge. The ether was decanted and the peptide was re-suspended infresh ether. The ether workup was repeated 3 additional times. Followingthe last ether wash, the peptide air dried to remove residual ether.

The peptide was dissolved in 10% acetonitrile and analyzed by massspectrometry and reverse-phase HPLC using a 30×4.6 cm C₁₈ column (Vydac;Hesperia, Calif., USA) with a gradient of 2-60% acetonitrile (0.1% TFA)over a 30 minute period. The described analysis indicated that theresulting product was ˜30% pure, the remainder being primarilynon-hydantoin containing product. Mass spectral analysis by electrosprayionization, indicated the mass of the main product to be 1218 da whichwas consistent with the expected, reduced product. The crude product(˜200 mg) was diluted to a concentration of 2 mg/mL in 5% acetic acid.To this solution, a 0.5 M iodine/methanol mixture was added drop-wisewith vigorous stirring until a pale yellow color was achieved. Thesolution was stirred vigorously for 10 minutes. Excess iodine wasquenched by adding 1.0 M sodium thiosulfate, under continuous mixing, tothe mixture until rendered colorless. The peptide was re-examined bymass spectrometry analysis and HPLC. The mass spectrometry analysisidentified a main species with a mass of 1216.4 da suggesting thesuccessful oxidation of the peptide. The peptide solution wasconcentrated to ˜10 mL using a centrifugal evaporator and purified on apreparative HPLC equipped with a C₁₈ column using a similar elutiongradient. The purified product was re-analyzed by HPLC for purity (>95%)and mass spectrometry (1216.4 da) and subsequently lyophilized.Following lyophilization, 18.4 mg of purified product was obtainedrepresenting a 7.5% yield.

Example 5:Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂

The peptide,Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂ wasassembled using Fmoc-chemistry on an Apex peptide synthesizer (AAPPTEC;Louisville, Ky., USA). In ten separate reaction wells of thesynthesizer, a 270 mg of 0.74 mmol/g (0.20 mmoles) Rink Amide MBHA resin(Novabiochem; San Diego, Calif., USA) aliquot was and pre-swollen in 3.0mL of dimethylformamide (DMF). Cycle 1: The resin was treated with two3.0 mL portions of 25% piperidine in DMF for 5 and 10 minutes intervals,respectively, followed by 4 washes of 3.0 mL DMF. Each wash consisted ofadding 3.0 mL of solvent, mixing for 1 minute and emptying for 1 minute.Amino acids stocks were prepared in N-methylpyrrolidinone (NMP) as 0.45M solutions containing 0.45 M N-hydroxybenzotriazole (HOBT).Diisopropylcarbodiimde (DIC) was prepared as a 0.5 M solution in NMP. Tothe de-blocked resin, 2.25 mL of the first amino acid (1.0 mmoles),i.e., Fmoc Cys(Trt)-OH (Novabiochem; San Diego, Calif., USA), was addedalong with 2.0 mL (1.0 mmoles) of DIC. After one hour of constantmixing, the reagents were drained and the coupling step repeated.Following amino acid acylation, the resin was washed with two 3.0 mLaliquots of DMF each wash lasting 1 minute. The above-described processsteps for the cycle 1, i.e., de-blocking, washing, acylating andwashing, were repeated for cycles 2-9 with the following amino acids:cycle 2: Fmoc-Trp(Boc)-OH (Genzyme; Cambridge, Mass., USA); cycle 3:Fmoc-Arg(Pbf)-OH (Novabiochem; San Diego, Calif., USA); cycle 4:Fmoc-D-Phe-OH (Genzyme; Cambridge, Mass., USA); cycle 5:Fmoc-His(Trt)-OH (Novabiochem; San Diego, Calif., USA); cycle 6:Fmoc-Glu(OtBu)-OH (Genzyme; Cambridge, Mass., USA) cycle 7:Fmoc-Cys(Trt)-OH, (Novabiochem; San Diego, Calif., USA); cycle 8:Fmoc-Gly-OH (Novabiochem; San Diego, Calif., USA); and cycle 9:Fmoc-Arg(Pbf)-OH (Genzyme; Cambridge, Mass., USA). The N-terminalFmoc-protecting group was removed with a solution of 25% piperidine inDMF followed by four 1 minute washes with 3.0 mL DMF. The resin waswashed four times with 3.0 mL DCM; each washing lasting approximately 1minute in duration. The resins from each of the 10 wells were combined.A small aliquot of the combined resin was obtained and the peptideattached thereto was de-protected and cleaved off so that the integrityof the main-chain assembly of the linear peptide could be determined byHPLC and MS analysis.

The peptide-resin was transferred to a 500 mL reaction vessel equippedwith a filter frit at the bottom. The resin was conditioned with severaldeciliters of DMF for several minutes which was drained off. A solutioncomprising 45 mL (86 eq) of 3.8 M diisopropylethylamine (DIPEA) indichloromethane (DCM) was then added followed by drop-wise addition of15.5 mL of 0.3 M (2.3 eq) of phenylchloroformate in DCM. The reactionvessel was gently mixed on an orbital shaker for 3 hours with gentlenitrogen bubbling. DCM was added periodically during the 3 hours ofmixing to replace DCM lost due to evaporation. The liquid portion wasthen drained off. The resin was washed with DMF several times andtreated for 10 minutes with a solution of 10 eq DIPEA in DMF which waslater drained off. The base treatment (DIPEA) formed the hydantoinmoiety with the concomitant liberation of p-nitrophenol, evident by thepresence of yellow colored solvent. The 10 minute base treatment wasrepeated until there was no longer evidence of p-nitrophenol beingreleased. The resin was washed with DMF followed by DCM.

To the resulting hydantoin-peptidyl resin, 80 mL of the followingreagent was added: 6% triisopropylsilane (TIS), 2% water, 5% (w/v)dithiothrieitol (DTT) and 87% trifluoroacetic acid (TFA) which wasallowed to mix for 4.5 hours. A filtrate was collected into 1000 mL ofcold anhydrous ethyl ether which was pelleted for 30 minutes in arefrigerated centrifuge at 4200 RPM. The ether was decanted. The peptidewas re-suspended in fresh ether and subjected to a secondcentrifugation. The ether was decanted and the peptide air dried toremove residual ether.

The peptide was dissolved in 10% acetonitrile for analysis by massspectrometry and reverse-phase HPLC, which was performed in a 30 minuteperiod with UV detection at 220 nm using a Luna C₁₈(2), 5@ 100 Å 250×4.6mm column (Phenomenex; Torrance, Calif., USA) having a gradient of 2-80%acetonitrile (0.1% TFA). This analysis identified a single major productthat was more than 70% pure. The non-hydantoin containing productaccounted for the remainder of the product. Mass was analyzed withelectrospray ionization techniques identifying ions of 407.2, 610.0 and1218.4 corresponding to the MH+3, MH+2 and MH+1 ions, respectively, ofmass 1218.4 da which was consistent with the desired linear product. Thecrude product (˜2.4 g) was diluted to a concentration of 2 mg/mL in 5%acetic acid. To this solution, 0.5 M iodine/methanol was added drop-wisewith vigorous stirring until a pale yellow color was observed. Thesolution was stirred vigorously for 10 minutes. Excess iodine wasquenched by adding 1.0 M sodium thiosulfate drop-wise with continuousmixing until the mixture was observed to be colorless. The peptide wasre-examined by mass spectrometry which identified the main specieshaving a mass of 1216.4 da evidencing the successful oxidation of thepeptide to the disulfide product. The peptide solution was concentratedto ˜500 mL using a centrifugal evaporator and then purified on apreparative HPLC equipped with a Luna C₁₈(2), 5@ 100 Å 250×21.2 mmpreparative HPLC column (Phenomenex; Torrance, Calif., USA) having anelution gradient of 10-50% acetonitrile (0.1% TFA) over 40 minutes withUV detection at 290 nm. The purified product was re-analyzed by HPLC forpurity (>99%). Additional mass spectrometry analysis indicated a productwith a mass of 1216.2 da consistent with the calculated molecular weightof the desired peptide 1216.4 da. Following lyophillization, 334 mg ofpurified product was obtained representing a 14% yield.

Additional compounds may be synthesized using the guidance of theexamples as detailed above, including, but not limited to, the followingcompounds:

-   -   cyclo[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH₂, which        has the following structure:

cyclo[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Lys]-NH₂, which has thefollowing structure:

-   -   cyclo[Hydantoin(C(O)-(Cys-D-Ala)-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C( ))-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH₂, which        has the following structure:

-   -   cyclo[Hydantoin(C)(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Ala-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        having which has the following structure:

-   -   [Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Nle-Ala))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys)-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(A6c-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(D-Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Leu-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Cha-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Aib-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys)]—NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(D-Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Aib-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Val-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Ile-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Leu-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C)(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

-   -   [Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)]-NH₂,        which has the following structure:

and

-   -   [Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)]-NH₂,        which has the following structure:

A selection of such compounds were subjected to both analytical HPLC andelectrospray mass spectrometry for characterization to ensure theidentity and purity, the results are provided in Table 1 depicted below.

TABLE 1 Molecular Weight and Purity for Selected Embodiments CalculatedExperimental Molecular Molecular Sequences Weight Weight Purity FORMULAI cyclo[Hydantoin(C(O)-(Asp-His))-D-2- 945.05 944.60 96.0%Nal-Arg-Trp-Lys]-NH₂ cyclo[Hydantoin(C(O)-(Cys-D-Ala))- 945.1 944.599.9% His-D-Phe-Arg-Trp-Cys]-NH₂ cyclo[Hydantoin(C(O)-(Glu-D-Ala))-980.1 979.46 99.9% His-D-Phe-Arg-Trp-Lys]-NH₂cyclo[Hydantoin(C(O)-(Glu-D-Ala))- 966.07 965.47 99.9%His-D-Phe-Arg-Trp-Orn]-NH₂ cyclo[Hydantoin(C(O)-(Glu-D-Ala))- 952.04951.55 95.5% His-D-Phe-Arg-Trp-Dab]-NH₂cyclo[Hydantoin(C(O)-(Glu-D-Ala))- 938.02 937.70 99.9%His-D-Phe-Arg-Trp-Dap]-NH₂ cyclo[Hydantoin(C(O)-(Asp-D-Ala))- 952.04951.55 98.7% His-D-Phe-Arg-Trp-Orn]-NH₂cyclo[Hydantoin(C(O)-(Asp-D-Ala))- 923.99 923.40 97.0%His-D-Phe-Arg-Trp-Dap]-NH₂ cyclo[Hydantoin(C(O)-(Asp-Aic))-D-2- 967.10966.60 99.9% Nal-Arg-Trp-Lys]-NH₂ cyclo[Hydantoin(C(O)-(Asp-A5c))-D-919.05 918.60 98.5% 2-Nal-Arg-Trp-Lys]-NH₂cyclo[Hydantoin(C(O)-(Asp-A6c))-D- 933.08 932.50 96.3%2-Nal-Arg-Trp-Lys]-NH₂ cyclo[Hydantoin(C(O)-(Asp-Apc))-D- 934.07 933.5098.7% 2-Nal-Arg-Trp-Lys]-NH₂ cyclo[Hydantoin(C(O)-(Asp-A3c))-D- 891.00890.50 95.8% 2-Nal-Arg-Trp-Lys]-NH₂ FORMULA IIHydantoin(C(O)-(Nle-Gly))-cyclo(Cys- 1173.34 1172.65 95.6%Glu-His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-1117.23 1116.54 98.2% Glu-His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(A6c-Nle))- 1183.42 1182.58 99.9%cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH₂ Hydantoin(C(O)-(D-Ala-Nle))-1129.33 1128.57 99.9% cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH₂Hydantoin(C(O)-(Val-Nle))-cyclo(Cys- 1157.39 1156.61 97.9%D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Leu-Nle))-cyclo(Cys-1171.41 1170.66 95.5% D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Cha-Nle))- 1211.48 1210.70 95.9%cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH₂Hydantoin(C(O)-(Aib-Nle))-cyclo(Cys- 1143.36 1142.80 99.9%D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-1115.31 1114.43 95.2% D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys- 1059.20 1058.55 99.9%D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-1143.36 1142.55 95.9% D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys- 1087.25 1086.55 99.9%D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂ Hydantoin(C(O)-(Ala-Gly))-cyclo(Cys-1073.22 1072.55 99.9% D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(D-Ala-Gly))- 1073.22 1073.00 98.2%cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH₂Hydantoin(C(O)-(Aib-Gly))-cyclo(Cys- 1087.25 1086.55 99.9%D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Val-Gly))-cyclo(Cys-1101.28 1100.65 96.9% D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Ile-Gly))-cyclo(Cys- 1115.31 1114.55 98.7%D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Leu-Gly))-cyclo(Cys-1115.31 1114.75 98.0% D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(D-Arg-Gly))- 1216.37 1216.10 97.7%cyclo(Cys-Glu-His-D-Phe-Arg-Trp- Cys)-NH₂ Hydantoin(C(O)-(Gly-D-Arg))-1216.37 1216.30 95.2% cyclo(Cys-Glu-His-D-Phe-Arg-Trp- Cys)-NH₂Hydantoin(C(O)-(Arg-Gly))- 1216.37 1216.20 99.9%cyclo(Cys-Glu-His-D-Phe-Arg-Trp- Cys)-NH₂ Hydantoin(C(O)-(Gly-Arg))-1216.37 1216.10 99.0% cyclo(Cys-Glu-His-D-Phe-Arg-Trp- Cys)-NH₂Hydantoin(C(O)-(Arg-Gly))- 1158.33 1158.70 99.0%cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH₂ Hydantoin(C(O)-(D-Arg-Gly))-1158.33 1158.70 97.0% cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH₂Hydantoin(C(O)-(Gly-D-Arg))- 1158.33 1158.70 95.0%cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH₂ Hydantoin(C(O)-(Gly-Arg))-1158.33 1158.70 98.0% cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH₂Hydantoin(C(O)-(Arg-Gly))- 1208.39 1208.00 99.9%cyclo(Cys-D-Ala-His-D-2-Nal-Arg- Trp-Cys)-NH₂ FORMULA IIIcyclo[Hydantoin(C(O)-(Aib-Cys))-D- 1030.20 1029.43 99.9%Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ cyclo[Hydantoin(C(O)-(Val-Cys))-D-1044.23 1043.46 95.4% Ala-His-D-Phe-Arg-Trp-Cys]-NH₂cyclo[Hydantoin(C(O)-(Leu-Cys))-D- 1058.25 1057.52 99.9%Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ cyclo[Hydantoin(C(O)-(Ile-Cys))-D-1058.25 1057.46 99.9% Ala-His-D-Phe-Arg-Trp-Cys]-NH₂cyclo[Hydantoin(C(O)-(A6c-Cys))-D- 1070.26 1069.60 99.9%Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-1060.18 1059.70 99.9% His-D-Phe-Arg-Trp-Cys]-NH₂

Melanocortin Functional Activity and Selectivity

The compounds of the present invention will interact preferentially(i.e., selectively) to MC-4 relative to the other melanocortinreceptors. Selectivity is particularly important when the compounds areadministered to humans or other animals to minimize the number of sideeffects associated with their administration. MC-4 selectivity of acompound is defined herein as the ratio of the EC₅₀ of the compound foran MC-1 receptor (EC₅₀-MC-1) over the EC₅₀ of the compound for the MC-3(EC₅₀-MC-3)/MC-4 (EC₅₀-MC-4) receptor, the EC₅₀ values being measured asdescribed above. The formulas are as follows:

MC-3 selectivity=[EC₅₀-MC-1]/[EC₅₀-MC-3]

MC-4 selectivity=[EC₅₀-MC-1]/[EC₅₀-MC-4]

A compound is defined herein as being “selective for the MC-3 receptor”when the above mentioned ratio “MC-3-selectivity” is at least about 10,preferably at least about 100, and more preferably at least about 500.

A compound is defined herein as being “selective for the MC-4 receptor”when the above mentioned ratio “MC-4-selectivity” is at least about 10,preferably at least about 100, and more preferably at least about 500.

One skilled in the art would know that procedures similar to thosedescribed herein may be used to assay the binding activities of thecompounds of the invention to melanocortin receptor molecules.

Cyclic AMP Bioassay

Intracellular cyclic AMP (cAMP) levels were determined by anelectrochemiluminescence (ECL) assay (Meso Scale Discovery®,Gaithersburg, Md.; referred to hereinafter as “MSD”). CHO-K1 cellsstably expressing the hMC receptor subtypes were suspended in RMPI 1640® assay buffer (RMPI 1640 buffer contains 0.5 mM isobutylmethylxanthine(IBMX) and 0.2% protein cocktail (MSD blocker A)). Transgenic CHO-K1cells stably expressing hMC receptor subtypes 1, 3, 4 or 5 weredispensed at a density of approximately 7,000 cells/well in 384-wellMulti-Array® plates (MSD) containing integrated carbon electrodes andcoated with anti-cAMP antibody. Increasing concentrations of the testcompounds were added and the cells were incubated for approximately 40minutes at approximately 37° C. Following this incubation, lysis buffer(HEPES-buffered saline solution with MgCl₂ and Triton X-100® at ph 7.3)containing 0.2% protein cocktail and 2.5 nM TAG™ ruthenium-labeled cAMP(MSD) was added and the cells were incubated for approximately 90minutes at room temperature. At the end of the second incubation periodread buffer (Tris-buffered solution containing an ECL co-reactant andTriton X-100 at ph 7.8) was added and the cAMP levels in the celllysates were immediately determined by ECL detection with a SectorImager 6000 Reader® (MSD). Data was analyzed using a computer-assistednon-linear regression analysis (XL fit; IDBS) and reported as either anEC₅₀ value or a Kb value.

EC₅₀ represents the concentration of an agonist compound needed toobtain 50% of the maximum reaction response, e.g., 50% of the maximumlevel of cAMP as determined using the assay described above.

A selection of compounds was tested using the above-discussed assays andthe cAMP bioassay data for selected compounds are reported in Tables 2A,2B and 2C.

TABLE 2A Intracellular Cyclic AMP (cAMP) Levels for Formula (I) ExamplesEC₅₀ EC₅₀ EC₅₀ EC₅₀ Formula (I) Compounds hMC1 hMC3 hMC4 hMC5cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂ — 218 5.42— cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂ — 22.33.62 — cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂ —39.2 4.94 — cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂56.7 18.2 0.182 >10000cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂ 56.6 88.64.50    9300cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂ — 49.3 2.12—

TABLE 2B Intracellular Cyclic AMP (cAMP) Levels for Formula (II)Examples EC₅₀ EC₅₀ EC₅₀ EC₅₀ Formula (II) Compounds hMC1 hMC3 hMC4 hMC5Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His- 54.3 12.2 0.177 >10000D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His- 1248.05 0.214 >10000 D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(A6c-Nle))-cyclo(Cys-D-Ala- — 4.89 1.80 —His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(D-Ala-Nle))-cyclo(Cys-D-Ala-— 2.56 1.47 — His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-D-Ala- — 4.61 0.977 —His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Leu-Nle))-cyclo(Cys-D-Ala- —9.68 1.83 — His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Cha-Nle))-cyclo(Cys-D-Ala- — 9.97 13.9 —His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-14.2 2.46 0.336    201 His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala- 17.0 21.5 0.584    352His-D-Phe-Arg-Trp-Pen)-NH₂ Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-40.2 8.90 0.495    8300 His-D-Phe-Arg-Trp-Pen)-NH₂Hydantoin(C(O)-(Ala-Gly))-cyclo(Cys-D-Ala- 17.6 2.23 0.241    516His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(D-Ala-Gly))-cyclo(Cys-D-Ala-4.70 2.22 0.309    355 His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-Glu- 18.0 17.1 0.160    2710His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-12.9 10.3 0.125    7440 His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His- 8.83 7.86 0.0979    4010D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His- 9.973.63 0.0687    335 D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala- 8.81 18.2 0.503    3560His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D- 11.523.2 0.513    3950 Ala-His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D- 7.53 11.6 0.435    9840Ala-His-D-Phe-Arg-Trp-Cys)-NH₂Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala- 8.85 5.17 0.599    3610His-D-Phe-Arg-Trp-Cys)-NH₂ Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-96.6 13.1 21.2    103 His-D-2-Nal-Arg-Trp-Cys)-NH₂

TABLE 2C Intracellular Cyclic AMP (cAMP) Levels for Formula (III)Examples EC₅₀ EC₅₀ EC₅₀ EC₅₀ Formula (III) Compounds hMC1 hMC3 hMC4 hMC5cyclo[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ — 6.280.407 — cyclo[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂— 3.77 0.214 —cyclo[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ — 4.720.428 — cyclo[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂— 8.51 1.85 —cyclo[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ — 5.661.72 — cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂14.5 21.8 0.576 1780

Radioligand Binding Assays

Cellular membranes used for the in vitro receptor binding assays wereobtained from transgenic CHO-K1 cells stably expressing hMC-R receptorsubtypes 1, 3, 4 or 5. The CHO-K1 cells expressing the desired hMC-Rreceptor type were sonicated (Branson® setting 7, approximately 30 sec)in ice-cold 50 mM Tris-HCl at pH 7.4 and then centrifuged at 39,000 gfor 10 minutes at approximately 4° C. The pellets were re-suspended inthe same buffer and centrifuged at 50,000 g for 10 minutes atapproximately 4° C. The washed pellets containing the cellular membraneswere stored at approximately −80° C.

Competitive inhibition of [¹²⁵I](Tyr²)-(Nle⁴-D-Phe⁷)α-MSH([¹²⁵I]-NDP-α-MSH, Amersham Biosciences®) binding was carried out inpolypropylene 96 well plates. Cell membranes (1-10 μg protein/well)prepared as described above were incubated in 50 mM Tris-HCl at pH 7.4containing 0.2% bovine serum albumin (BSA), 5 mM MgCl₂, 1 mM CaCl₂ and0.1 mg/mL bacitracin, with increasing concentrations of the testcompound and 0.1-0.3 nM [¹²⁵I]-NDP-α-MSH for approximately 90-120minutes at approximately 37° C. Bound [¹²⁵I]-NDP-α-MSH ligand wasseparated from free [¹²⁵I]-NDP-α-MSH by filtration through GF/C glassfiber filter plates (Unifilter®; Packard) presoaked with 0.1% (w/v)polyethylenimine (PEI), using a Packard Filtermate® harvester. Filterswere washed three times with 50 mM Tris-HCl at pH 7.4 at a temperatureof approximately 0-4° C. and then assayed for radioactivity using aPackard Topcount® scintillation counter. Binding data were analyzed bycomputer-assisted non-linear regression analysis (XL fit; IDBS).

A selection of the preferred embodiments was tested using theabove-discussed assay and the binding constants (Ki in nM) are reportedin Tables 3A, 3B and 3C.

TABLE 3A Binding Constants for Formula (I) Examples Ki Ki Ki Ki Formula(I) Compounds hMC1 hMC3 hMC4 hMC5cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂ 230 7590126    7020 cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂72.6 1920 45.2 >10000cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂ 60.4 284052.4 >10000 cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂28 90.5 12.7    877cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂ 16.4 8634.97 >10000 cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂37.7 576 7.81    6400cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂ 66.6 182019.9 >10000 cyclo[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH₂ 20068.8 6.63    142cyclo[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH₂ 9028 2628 35.8   1156 cyclo[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH₂ 99382390 44.6    1103cyclo[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH₂ 2170 1479 16.5   451 cyclo[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH₂ 12762756 266    1096cyclo[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH₂ 7567 1922 420   2879

TABLE 3B Binding Constants for Formula (II) Examples Ki Ki Ki Ki Formula(II) Compounds hMC1 hMC3 hMC4 hMC5Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂ 14.3198 5.76 67.8Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂ 11.9311 5.41 73.9Hydantoin(C(O)-(A6c-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂31.6 224 19.6 2500Hydantoin(C(O)-(D-Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂16.0 63.9 8.64 1820Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂33.7 132 40.2 3210Hydantoin(C(O)-(Leu-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂48.3 534 74.1 3290Hydantoin(C(O)-(Cha-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂40.8 870 137 3560Hydantoin(C(O)-(Aib-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂17.7 73.6 8.40 2120Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂7.92 46.4 6.70 21.3Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂20.9 69.7 8.32 50.0Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂12.9 38.5 3.53 27.1Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂ 127811 10.4 381Hydantoin(C(O)-(Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂13.9 38.4 5.73 18.9Hydantoin(C(O)-(D-Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂11.7 73.1 4.28 34.7Hydantoin(C(O)-(Aib-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂36.8 290 13.7 133Hydantoin(C(O)-(Val-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂15.3 160 8.66 33.4Hydantoin(C(O)-(Ile-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂11.6 194 11.5 28.9Hydantoin(C(O)-(Leu-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂19.3 331 26.7 44.6Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂9.49 124 2.95 2260Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂4.30 78.0 1.77 4540Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂ 8.5994.1 2.44 7760Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂ 5.6855.5 2.44 4220Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂2.65 41.3 4.17 650Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂3.52 48.7 5.78 872Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂3.51 29.2 6.04 914Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂1.14 01.7 4.53 783Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂11.9 7.43 0.195 14.6

TABLE 3C Binding Constants for Formula (III) Examples Ki Ki Ki KiFormula (III) Compounds hMC1 hMC3 hMC4 hMC5cyclo[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ 47.61100 47.1 >10000cyclo[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ 21.2730 34.5 >10000cyclo[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ 47.41550 27.9 >10000cyclo[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ 53.41760 41.6 >10000cyclo[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂ 38.51760 53.2    9270cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂ 15.6 3058.92    3070

In Vivo Assays

Ligands for melanocortin receptors of the present invention can be andwere tested for an effect upon food intake and/or body weight accordingto the following procedures. One skilled in the art would know thatprocedures similar to those described herein may be used to assay theeffect of the compounds of the invention upon food intake and/or bodyweight.

Acute Feeding Experiments (Fasting)

Male Sprague Dawley rats (250 g) are housed in individual cages andmaintained under 12:12 hour light:dark conditions. The rats are fastedfor 18 hours prior to the start of the experiment with water availablead libitum. At time 0, the rats are injected subcutaneously (sc) withselected compounds at selected doses, for example, 500 or 100 nmole/kg,or with vehicle, and are provided with food. Individual food consumptionis measured at about 1, 2, 3, 4, 5 and 6 hours after injection.

Acute Feeding Experiments (Non Fasting)

Male Sprague Dawley rats (250 g) were housed in individual cages andmaintained under 12:12 hour light:dark conditions. Food and water wasavailable ad libitum throughout the experiment. At time 0, the rats wereinjected sc with compound at doses of either 8 mole/kg, or with vehicle.Individual food consumption was measured at about 0.5, 1, 1.5, 2, 3 and4 hours after injection. Data for selected compounds of the inventionare reported in FIG. 1.

Chronic Feeding Experiments

Male Sprague Dawley rats (250 g) were housed in individual cages andmaintained under 12:12 hour light:dark conditions with both food andwater available ad libitum. The rats were injected 3×/day (0800, 1200,and 1600 h), sc, with compound at various doses or with vehicle for 7days. Individual body weight and food consumption were measured daily.Data for selected compounds of the invention are reported in FIGS. 2A,2B, 3A, 3B, 4A and 4B.

Methods of Use and Compositions

Based on their ability to agonize or antagonize the MC-4 and/or MC-3receptor, the present inventions also relates to the use of the ligandsof the present invention in methods for treating obesity as well asother body weight disorders (e.g., anorexia, bulimia, AIDS wasting,wasting in frail elderly, Prader-Willi syndrome) and cachexia (e.g.,cancer cachexia, renal cachexia, cardiac cachexia). The inventionfurther relates to the treatment of disorders relating to behavior(e.g., motivation, anxiety, depression, neuropathic pain), memory(including learning), cardiovascular function (e.g. cardiac cachexia),pulmonary disorders (e.g., acute respiratory distress syndrome,pulmonary fibrosis, chronic obstructive pulmonary disease, asthma),inflammation (e.g., rheumatoid arthritis, gouty arthritis, multiplesclerosis), sepsis and septic, cardiogenic and hypovolemic shock, sexualdysfunction (e.g., endometriosis, uterine bleeding), penile erection,muscle atrophy, bone development, nerve growth, protection and repair(spinal cord injuries), intrauterine fetal growth, and the like. Inaddition, formula (I), (II) or (III) compounds may ameliorate insult toa patient (e.g., organ transplant rejection, ischemia and reperfusioninjury, wounding) or weight loss cause by a medicinal regimen (e.g.,chemotherapy, radiation therapy, temporary or permanent immobilization,dialysis). Modulation of normal body functions (e.g., ovarian andplacental development, prolactin and FSH secretion, parturition,spermatogenesis, thyroxin release, aldosterone synthesis, bodytemperature, blood pressure, heart rate, vascular tone, brain bloodflow, blood glucose levels, sebum and pheromone secretion) is possiblewith the claimed compounds.

The present invention provides a method of inhibiting alcoholconsumption, for reducing alcohol consumption, for treating alcoholism,or for treating alcohol abuse by eliciting an agonist or antagonisteffect from a melanocortin receptor by administering an effective amountof a compound of formula (I), (II) or (III), or a pharmaceuticallyacceptable salt thereof. The formula (I), (II) or (III) compounds areuseful for inhibiting alcohol consumption is a selective melanocortin-4receptor agonist, or a pharmaceutically acceptable salt thereof, with afunctional activity characterized by an EC₅₀ at least 15-fold more, atleast 17-fold more, at least 90-fold more, at least 200-fold more or atleast 3000-fold more selective for the human melanocortin-4 receptorthan for the human melanocortin-1 receptor, the human melanocortin-3receptor and the human melanocortin-5 receptor.

The terms treating and treatment are used herein to mean that, at aminimum, administration of a compound of the present invention mitigatesa disease state by acting via the MC-3 or MC-4 receptor. Thus, the termsinclude: preventing a disease state from occurring in a mammal,particularly when the mammal is predisposed to acquiring the disease,but has not yet been diagnosed with the disease; inhibiting progressionof the disease state; and/or alleviating or reversing the disease state.

The invention compounds can therefore be formulated into pharmaceuticalcompositions for use in treatment or prophylaxis of these conditions.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., latest edition and Peptide and Protein DrugDelivery, Marcel Dekker, N.Y., 1991.

The compositions of the invention comprise:

-   -   a. a safe and effective amount of a compound of formula        (I), (II) or (III); and    -   b. a pharmaceutically-acceptable excipient.

A “safe and effective amount” of a formula (I), (II) or (III) compoundis an amount that is effective to interact with the MC-4 and/or MC-3receptor, in an animal, preferably a mammal, more preferably a humansubject, without undue adverse side effects (such as toxicity,irritation, or allergic response), commensurate with a reasonablebenefit/risk ratio when used in the manner of this invention. Thespecific “safe and effective amount” will, obviously, vary with suchfactors as the particular condition being treated, the physicalcondition of the patient, the duration of treatment, the nature ofconcurrent therapy (if any), the specific dosage form to be used, theexcipient employed, the solubility of the formula (I), (II) or (III)compound therein, and the dosage regimen desired for the composition.

In addition to the subject compound, the compositions of the subjectinvention contain one or more pharmaceutically-acceptable excipients.The term “pharmaceutically-acceptable excipient”, as used herein, meansone or more compatible solid or liquid ingredients which are suitablefor administration to an animal, preferably a mammal, more preferably ahuman. The term “compatible”, as used herein, means that the componentsof the composition are capable of being commingled with the subjectcompound, and with each other, in a manner such that there is nointeraction which would substantially reduce the pharmaceutical efficacyof the composition under ordinary use situations.Pharmaceutically-acceptable excipients must, of course, be ofsufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the animal, preferably a mammal, morepreferably a human being treated.

Some examples of substances which can serve aspharmaceutically-acceptable excipients or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; vegetable oils, such as peanut oil, cottonseedoil, sesame oil, olive oil, corn oil and oil of theobroma; polyols suchas propylene glycol, glycerin, sorbitol, mannitol, and polyethyleneglycol; agar; alginic acid; wetting agents and lubricants, such assodium lauryl sulfate; coloring agents; flavoring agents; tabletingagents, stabilizers; antioxidants; preservatives; pyrogen-free water;isotonic saline; and buffers, such as phosphate, citrate and acetate.

The choice of pharmaceutically-acceptable excipients to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered. If the subject compound is to beinjected, the preferred pharmaceutically-acceptable excipient is sterilewater, physiological saline, or mixtures thereof, the pH of which haspreferably been adjusted to about 4-10 with a pharmaceutical buffer; acompatible suspending agent may also be desirable.

In particular, pharmaceutically-acceptable excipients for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, lactose, vegetable oils, syntheticoils, polyols, alginic acid, phosphate, acetate and citrate buffersolutions, emulsifiers, isotonic saline, and pyrogen-free water.Preferred excipients for parenteral administration include propyleneglycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably,the pharmaceutically-acceptable excipient, in compositions forparenteral administration, comprises at least about 90% by weight of thetotal composition.

The compositions of this invention are preferably provided in unitdosage form. As used herein, a “unit dosage form” is a composition ofthis invention containing an amount of a formula (I), (II) or (III)compound that is suitable for administration to an animal, preferably amammal, more preferably a human subject, in a single dose, according togood medical practice. These compositions preferably contain from about1 mg to about 750 mg, more preferably from about 3 mg to about 500 mg,still more preferably from about 5 mg to about 300 mg, of a formula (I),(II) or (III) compound.

The compositions of this invention may be in any of a variety of forms,suitable (for example) for oral, rectal, topical, nasal, ocular,transdermal, pulmonary or parenteral administration. Depending upon theparticular route of administration desired, a variety ofpharmaceutically-acceptable excipients well-known in the art may beused. These include solid or liquid fillers, diluents, hydrotropes,surface-active agents, and encapsulating substances. Optionalpharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the formula (I),(II) or (III) compound. The amount of excipient employed in conjunctionwith the formula (I), (II) or (III) compounds is sufficient to provide apractical quantity of material for administration per unit dose of thecompound. Techniques and compositions for making dosage forms useful inthe methods of this invention are described in the following references,all incorporated by reference herein: Modern Pharmaceutics, Chapters 9and 10 (Banker & Rhodes, editors, 1979); Lieberman et al.,Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction toPharmaceutical Dosage Forms 2d Edition (1976).

Various oral dosage forms can be used, including such solid forms astablets, capsules, multi-particulars, gels, films, ovules, elixirs,granules and bulk powders. These oral forms comprise a safe andeffective amount, usually at least about 5%, and preferably from about25% to about 50%, of the formula (I), (II) or (III) compound. Tabletscan be compressed, tablet triturates, enteric-coated, sugar-coated,film-coated, or multiple-compressed, containing suitable binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Liquid oral dosageforms include aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules, andeffervescent preparations reconstituted from effervescent granules,containing suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, melting agents, coloring agentsand flavoring agents.

The pharmaceutically-acceptable excipient suitable for the preparationof unit dosage forms for peroral administration are well-known in theart. Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, dibasic calciumphosphate, sodium carbonate, sodium citrate, mannitol, lactose andcellulose; binders such as starch, gelatin, polyvinyl pyrrolidone,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),acacia and sucrose; disintegrants such as starch (preferably corn,potato or tapioca), sodium starch, glycollate, alginic acid, complexsilicates and croscarmelose; lubricants such as magnesium stearate,stearic acid, glyceryl behenate and talc. Glidants such as silicondioxide can be used to improve flow characteristics of the powdermixture. Coloring agents, such as the FD&C dyes, can be added forappearance. Sweeteners and flavoring agents, such as aspartame,saccharin, menthol, peppermint, and fruit flavors, are useful adjuvantsfor chewable tablets. Capsules typically comprise one or more soliddiluents disclosed above. The selection of excipient components dependson secondary considerations like taste, cost, and shelf stability, whichare not critical for the purposes of the subject invention, and can bereadily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable excipientssuitable for preparation of such compositions are well known in the art.Typical components of excipients for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, tragacanth and sodium alginate; typical wetting agentsinclude lecithin and polysorbate 80; and typical preservatives includemethyl paraben, propyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Modified release and pulsatile release dosage forms may containexcipients such as those detailed for immediate-, delayed-, modified-,sustained-, pulsed- or controlled-released in the gastrointestinal tractin the vicinity of the desired topical application, or at various timesto extend the desired action, together with additional excipients thatact as release rate modifiers, these being coated by conventionalmethods, typically with pH or time-dependent coatings, on and/orincluded in the body of the device. Release rate modifiers include, butare not exclusively limited to, hydroxypropyl methyl cellulose,hydroxypropyl methyl cellulose phthalate, methyl cellulose, sodiumcarboxymethylcellulose, ethyl cellulose, cellulose acetate, celluloseacetate phthalate, polyvinylacetate phthalate, polyethylene oxide,xanthan gum, carbomer, ammonio methacrylate copolymer, hydrogenatedcastor oil, carnauba wax, paraffin wax, cellulose acetate phthalate,hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer andmixtures thereof. Modified release and pulsatile release dosage formsmay contain one or a combination of release rate modifying excipients.Release rate modifying excipients may be present both within the dosageform i.e. within the matrix, and/or on the dosage form, i.e. upon thesurface or coating.

The compounds of the invention may also be administered asfast-dispersing or fast-dissolving dosage forms (FDDFs). Suchformulations may contain the following ingredients: aspartame,acesulfame potassium, citric acid, croscarmellose sodium, crospovidone,diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin,hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methylmethacrylate, mint flavoring, polyethylene glycol, fumed silica, silicondioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol,xylitol. The terms “dispersing” or “dissolving” as used herein todescribe FDDFs, are dependent upon the solubility of the drug substanceused, i.e., where the drug substance is insoluble a fast dispersingdosage form can be prepared and where the drug substance is soluble afast dissolving dosage form can be prepared.

Because the compounds of the present invention are peptides in nature, apreferred mode of administration is parenteral (more preferablyintravenous injection) in the form of a unit dose form. Preferred unitdose forms include suspensions and solutions, comprising a safe andeffective amount of a formula I, (II) or (III) compound. For suchparenteral administration, they are best used in the form of a sterileaqueous solution which may contain other substances, for example, enoughsalts or glucose to make the solution isotonic with blood. The aqueoussolutions should be suitably buffered (preferably to a pH of from 3 to9), if necessary. The preparation of suitable parenteral formulationsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well-known to those skilled in the art.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.When administered intranasally or by inhalation, compounds of formula(I), (II) or (III) are conveniently delivered in the form of a drypowder inhaler or an aerosol spray presentation from a pressurizedcontainer, pump, spray, atomizer or nebulae, with or without the use ofa suitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134A®) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA®), carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Thepressurized container, pump, spray, atomizer or nebulizer may contain asolution or suspension of the active compound, e.g. using a mixture ofethanol and the propellant as the solvent, which may additionallycontain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges(made, for example, from gelatin) for use in an inhaler or insufflatormay be formulated to contain a powder mix of a compound of the inventionand a suitable powder base such as lactose or starch.

Aerosol or dry powder formulations are preferably arranged so that eachmetered dose or “puff” contains from 1 to 50 mg of a compound of theinvention for delivery to the patient. The overall daily dose with anaerosol will be in the range of from 1 to 50 mg which may beadministered in a single dose or, more usually, in divided dosesthroughout the day.

Alternatively, the compounds of the invention can be administered in theform of a suppository or pessary, or they may be applied topically inthe form of a gel, hydrogel, lotion, solution, cream, ointment ordusting powder. The compounds of the invention may also be dermally ortransdermally administered, for example, by the use of a skin patch.They may also be administered by the pulmonary, vaginal or rectalroutes.

They may also be administered by the ocular route, particularly fortreating disorders of the eye. For ophthalmic use, the compounds can beformulated as micronized suspensions in isotonic, pH-adjusted, sterilesaline, or, preferably, as solutions in isotonic, pH-adjusted, sterilesaline, optionally in combination with a preservative such as abenzylalkonium chloride. Alternatively, they may be formulated in anointment such as petrolatum.

For application topically to the skin, the compounds of the inventioncan be formulated as a suitable ointment containing the active compoundsuspended or dissolved in, for example, a mixture with one or more ofthe following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water. Alternatively, they can be formulated as a suitablelotion or cream, suspended or dissolved in, for example, a mixture ofone or more of the following: mineral oil, sorbitan monostearate, apolyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the invention may also be used in combination with acyclodextrin. Cyclodextrins are known to form inclusion andnon-inclusion complexes with drug molecules. Formation of adrug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g., asa carrier, diluent or solubilizer. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described in WO91/11172 (Stella et al., 1991), WO 94/02518 (Stella et al., 1994) and WO98/55148 (Vandecruys, 1998).

For treating cardiovascular disorders, particular hypertension, thecompounds of the invention may be combined with one or more activeingredient selected from the list:

-   -   a) angiotensin receptor blockers (ARB), such as losartan,        valsartan, telmisartan, candesartan, irbesartan, eprosartan and        olmesartan;    -   b) calcium channel blockers (CCB) such as amlodipine;    -   c) statins, such as atorvastatin;    -   d) PDE5 inhibitors, such as sildenafil, tadalafil, vardenafil,        5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;        5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-di-hydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        and; the pyrazolo[4,3-d]pyrimidin-4-ones disclosed in WO        00/27848 particularly        N-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-yl)-4-propxyphenyl]sulfonyl]-1-methyl2-pyrrolidinepropanamide        [DA-8159 (Example 68 of WO 00/27848 (Yoo et al., 2000))];    -   e) beta blockers, such as atenolol or carvedilol;    -   f) ACE inhibitors, such as quinapril, enalapril and lisinopril;    -   g) alpha-blockers such as doxazosin;    -   h) selective aldosterone receptor antagonists (SARA), such as        eplerenone or spironolactone;    -   i) imidazoline I₁ agonists, such as rilmenidine or monoxidine;        and    -   j) endothelin receptor antagonists and endothelin converting        enzyme inhibitors.

Compositions of the subject invention may optionally include other drugactives. If a combination of active agents are administered, then theymay be administered simultaneously, separately or sequentially.

Methods of Administration

As indicated, compositions of this invention can be administeredtopically or systemically. Systemic application includes any method ofintroducing a formula (I), (II) or (III) compound into the tissues ofthe body, e.g., intra-articular, intrathecal, epidural, intramuscular,transdermal, intravenous, intraperitoneal, subcutaneous, sublingual,rectal, nasal, pulmonary, and oral administration. The formula (I), (II)or (III) compounds of the present invention are preferably administeredsystemically, more preferably parenterally and most preferably viaintravenous injection.

The specific dosage of compound to be administered, as well as theduration of treatment, and whether the treatment is topical or systemicare interdependent. The dosage and treatment regimen will also dependupon such factors as the specific formula (I), (II) or (III) compoundused, the treatment indication, the ability of the formula (I), (II) or(III) compound to reach minimum inhibitory concentrations at the site ofthe metalloprotease to be inhibited, the personal attributes of thesubject (such as weight), compliance with the treatment regimen, and thepresence and severity of any side effects of the treatment.

Typically, for a human adult (weighing approximately 70 kilograms), fromabout 0.003 mg to about 300 mg, more preferably from about 0.03 mg toabout 100 mg, of formula (I), (II) or (III) compound are administeredper day for systemic administration. It is understood that these dosageranges are by way of example only, and that daily administration can beadjusted depending on the factors listed above.

As is known and practiced in the art, all formulations for parenteraladministration must be sterile. For mammals, especially humans,(assuming an approximate body weight of 70 kilograms) individual dosesof from about 0.001 mg. to about 100 mg are preferred.

A preferred method of systemic administration is intravenous delivery.Individual doses of from about 0.01 mg to about 100 mg, preferably fromabout 0.1 mg to about 100 mg, are preferred when using this mode ofdelivery.

In all of the foregoing, of course, the compounds of the invention canbe administered alone or as mixtures, and the compositions may furtherinclude additional drugs or excipients as appropriate for theindication.

The compound of the invention can be delivered to the preferred site inthe body by using a suitable drug delivery system. Drug delivery systemsare well known in the art. For example, a drug delivery technique usefulfor the compounds of the present invention is the conjugation of thecompound to an active molecule capable of being transported through abiological barrier (Zlokovic, B. V., Pharma. Res., 12:1395-406 (1995)).A specific example constitutes the coupling of the compound of theinvention to fragments of insulin to achieve transport across the bloodbrain barrier (Fukuta, M. et al., Pharma. Res., 11:1681-8 (1994)). Forgeneral reviews of technologies for drug delivery suitable for thecompounds of the invention (Zlokovic, B. V., Pharma. Res., 12:1395-406(1995) and Pardridge, W. M., Pharmacol. Toxicol., 71:3-10 (1992).

1. A compound of formula

wherein X is selected from the group consisting of —CH₂—S—S—CH₂—,—C(CH₃)₂—S—S—CH₂—, —CH₂—S—S—C(CH₃)₂—, —C(CH₃)₂—S—S—C(CH₃)₂—,—(CH₂)₂—S—S—CH₂—, —CH₂—S—S—(CH₂)₂—, —(CH₂)₂—S—S—(CH₂)₂—,—C(CH₃)₂—S—S—(CH₂)₂—, —(CH₂)₂—S—S—C(CH₃)₂,—(CH₂)_(t)—C(O)—NR⁸—(CH₂)_(r)— and —(CH₂)_(r)—NR⁸—C(O)—(CH₂)_(t)—; R¹and R² each is, independently for each occurrence thereof, H,(C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; R³ is —OH or —NH₂; R⁴ and R⁵each is, independently for each occurrence thereof, H, (C₁-C₁₀)alkyl orsubstituted (C₁-C₁₀)alkyl; X¹ is

A¹ is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, (X¹, X², X³, X⁴,X⁵)Phe or deleted; A² is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X¹, X²,X³, X⁴, X⁵)Phe; A³ is Arg, hArg, Dab, Dap, Lys or Orn; A⁴ is Bal, 1-Nal,2-Nal, (X¹, X², X³, X⁴, X⁵)Phe or Trp; R⁶ and R⁷ each is, independentlyfor each occurrence thereof, H, (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl,aryl(C₁-C₅)alkyl, substituted (C₁-C₁₀)alkyl, substituted(C₁-C₁₀)heteroalkyl or substituted aryl(C₁-C₅)alkyl or R⁶ and R⁷ may bejoined together form a cyclic moiety; R⁸ is H, (C₁-C₁₀)alkyl orsubstituted (C₁-C₁₀)alkyl; r is, independently for each occurrencethereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrencethereof, 1 or 2; or a pharmaceutically acceptable salt thereof.
 2. Acompound according claim 1 wherein the compound iscyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ IDNO:1) cyclo[Hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂;(SEQ ID NO:2)cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH₂; (SEQ IDNO:1) cyclo[Hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH₂;(SEQ ID NO:2)cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ IDNO:3) cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂; (SEQID NO:4) cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂;(SEQ ID NO:4)cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂; (SEQ IDNO:4) cyclo[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ IDNO:5) cyclo[Hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ IDNO:5) cyclo[Hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ IDNO:6) cyclo[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ IDNO:7) cyclo[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ IDNO:8) cyclo[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ IDNO:6) cyclo[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ IDNO:7) cyclo[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ IDNO:8) cyclo[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ IDNO:9) cyclo[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ IDNO:10) cyclo[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ IDNO:9) cyclo[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ IDNO:10) cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂;(SEQ ID NO:68)cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂; (SEQ IDNO:11) cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂;(SEQ ID NO:11)cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂; (SEQ IDNO:11) cyclo[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH₂; (SEQ IDNO:12) or cyclo[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQID NO:61) or a pharmaceutically acceptable salt thereof.
 3. A compoundof formula (II)

wherein X¹ is

X₂ is

A¹ is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen; A² is anL- or D-amino acid; A³ is His, 2-Pal, 3-Pal, 4-Pal, (X¹, X², X³, X⁴,X⁵)Phe, Taz, 2-Thi or 3-Thi; A⁴ is D-Bal, D-1-Nal, D-2-Nal, D-Phe orD-(X¹, X², X³, X⁴, X⁵)Phe; A⁵ is Arg, hArg, Dab, Dap, Lys or Orn; A⁶ isBal, 1-Nal, 2-Nal, (X¹, X², X³, X⁴, X⁵)Phe or Trp; A⁷ is Asp, Cys,D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen; R¹ is H, (C₁-C₁₀)alkyl orsubstituted (C₁-C₁₀)alkyl; R² and R³ each is, independently, H,(C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted(C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substitutedaryl(C₁-C₅)alkyl or R² and R³ may be joined together form a cyclicmoiety; R⁴ is CO₂H or C(O)NH₂; R⁵ and R⁶ each is, independently, H,(C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted(C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substitutedaryl(C₁-C₅)alkyl or R⁵ and R⁶ may be joined together form a cyclicmoiety; R⁷ and R⁸ each is, independently, H, (C₁-C₁₀)alkyl,(C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted (C₁-C₁₀)alkyl,substituted (C₁-C₁₀)heteroalkyl or substituted aryl(C₁-C₅)alkyl; or R⁷and R⁸ may be joined together form a cyclic moiety; R⁹ is H,(C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; and n is, independently foreach occurrence thereof, 1, 2, 3, 4, 5, 6 or 7; or a pharmaceuticallyacceptable salt thereof.
 4. A compound according to claim 3 wherein saidcompound is:Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:13)Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:14)Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:15)Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:16)Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:17)Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;(SEQ ID NO:18)Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;(SEQ ID NO:19)Hydantoin(C(O)-(Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:20)Hydantoin(C(O)-(D-Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:21)Hydantoin(C(O)-(Aib-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:22)Hydantoin(C(O)-(Val-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:23)Hydantoin(C(O)-(Ile-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:24)Hydantoin(C(O)-(Leu-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:25)Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂;(SEQ ID NO:15)Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂;(SEQ ID NO:14)Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:26)Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:27)Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:28)Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;(SEQ ID NO:27)Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;(SEQ ID NO:28Hydantoin(C(O)-(Ala-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:29)Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:30)Hydantoin(C(O)-(Gly-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:31)Hydantoin(C(O)-(A6c-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:32)Hydantoin(C(O)-(Gly-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:33)Hydantoin(C(O)-(Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:34)Hydantoin(C(O)-(D-Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:35)Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:36)Hydantoin(C(O)-(Leu-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:37)Hydantoin(C(O)-(Cha-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:38)Hydantoin(C(O)-(Aib-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:39)Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:40)Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂;(SEQ ID NO:40)Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:41)Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;(SEQ ID NO:41)Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:42)Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:42)Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:43)Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;(SEQ ID NO:43) or Hydantoin(C(O)-(Nle-Ala))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ IDNO:44) or a pharmaceutically acceptable salt thereof.
 5. A compound offormula (III)

wherein X is selected from the group consisting of —CH₂—S—S—CH₂—,—C(CH₃)₂—S—S—CH₂—, —CH₂—S—S—C(CH₃)₂—, —C(CH₃)₂—S—S—C(CH₃)₂—,—(CH₂)₂—S—S—CH₂—, —CH₂—S—S—(CH₂)₂, —(CH₂)₂—S—S—(CH₂)₂—,—C(CH₃)₂—S—S—(CH₂)₂—, —(CH₂)₂—S—S—C(CH₃)₂—,—(CH₂)_(t)—C(O)—NR⁸—(CH₂)_(r)— and —(CH₂)_(r)— NR⁸—C(O)—(CH₂)_(t)—; R¹and R⁵ each is, independently, H, (C₁-C₁₀)alkyl or substituted(C₁-C₁₀)alkyl; R² and R³ each is, independently, H, (C₁-C₁₀)alkyl,(C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted (C₁-C₁₀)alkyl,substituted (C₁-C₁₀)heteroalkyl or substituted aryl(C₁-C₅)alkyl or R²and R³ may be joined together to form a ring; R⁴ is —OH or —NH₂; R⁶ andR⁷ each is, independently, H, (C₁-C₁₀)alkyl or substituted(C₁-C₁₀)alkyl; A¹ is an L- or D-amino acid or deleted; A² is His, 2-Pal,3-Pal, 4-Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Taz, 2-Thi or 3-Thi; A³ is D-Bal,D-1-Nal, D-2-Nal, D-Phe or D-(X¹,X²,X³,X⁴,X⁵)Phe; A⁴ is Arg, hArg, Dab,Dap, Lys or Orn; A⁵ is Bal, 1-Nal, 2-Nal, (X¹,X²,X³,X⁴,X⁵)Phe or Trp; ris, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and tis, independently for each occurrence thereof, 1 or 2; or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 5 wherein said compound is:cyclo[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:46)cyclo[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:45)cyclo[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:47)cyclo[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:48)cyclo[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:49)cyclo[Hydantoin(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:50)cyclo[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:51)cyclo[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:52)cyclo[Hydantoin(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:53)cyclo[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:54)cyclo[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:55)cyclo[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQID NO:56) orcyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ IDNO:57) or a pharmaceutically acceptable salt thereof.
 7. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to any one of claims 1 to 6 and apharmaceutically acceptable carrier or diluent; or a pharmaceuticallyacceptable salt thereof.
 8. A pharmaceutical composition according toclaim 7, wherein said compound is a selective melanocortin-4 receptoragonist; or a pharmaceutically acceptable salt thereof.
 9. Apharmaceutical composition according to claim 8, wherein said compoundis a selective melanocortin-4 receptor agonist with a functionalactivity characterized by an EC₅₀ at least 15-fold more selective forthe human melanocortin-4 receptor than for the human melanocortin-1receptor, the human melanocortin-3 receptor and the human melanocortin-5receptor; or a pharmaceutically acceptable salt thereof.
 10. Apharmaceutical composition according to claim 9, wherein the functionalactivity of the melanocortin-4 receptor agonist is characterized by anEC₅₀ at least 17-fold more selective for the human melanocortin-4receptor than for the human melanocortin-3 receptor; or apharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition according to claim 9, wherein the functional activity of themelanocortin-4 receptor agonist is characterized by an EC₅₀ at least90-fold more selective for the human melanocortin-4 receptor than forthe human melanocortin-3 receptor; or a pharmaceutically acceptable saltthereof.
 12. A pharmaceutical composition according to claim 9, whereinthe functional activity of the melanocortin-4 receptor agonist ischaracterized by an EC₅₀ at least 200-fold more selective for the humanmelanocortin-4 receptor than for the human melanocortin-5 receptor; or apharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition according to claim 9, wherein the functional activity of themelanocortin-4 receptor agonist is characterized by an EC₅₀ at least3000-fold more selective for the human melanocortin-4 receptor than forthe human melanocortin-5 receptor; or a pharmaceutically acceptable saltthereof.
 14. A method of eliciting an agonist or antagonist effect froma melanocortin receptor in a subject in need thereof which comprisesadministering to said subject a therapeutically effective amount of acompound according to any one of claims 1 to 6, or a pharmaceuticallyacceptable salt thereof.
 15. A method according to claim 14, whereinsaid compound is a selective melanocortin-4 receptor agonist.
 16. Amethod according to claim 15, wherein said compound is a selectivemelanocortin-4 receptor agonist with a functional activity characterizedby an EC₅₀ at least 15-fold more selective for the human melanocortin-4receptor than for the human melanocortin-1 receptor, the humanmelanocortin-3 receptor and the human melanocortin-5 receptor.
 17. Amethod according to claim 16, wherein the functional activity of themelanocortin-4 receptor agonist is characterized by an EC₅₀ at least17-fold more selective for the human melanocortin-4 receptor than forthe human melanocortin-3 receptor.
 18. A method of treating a disease ormedical condition by eliciting an agonist or antagonist effect from amelanocortin receptor according to claim 14, wherein said disease orcondition is selected from the group consisting of: generalinflammation, inflammatory bowel disease, brain inflammation, sepsis andseptic shock; rheumatoid arthritis, gouty arthritis and multiplesclerosis; a metabolic disease or medical condition accompanied byweight gain, obesity, feeding disorders and Prader-Willi Syndrome; ametabolic disease or medical condition accompanied by weight loss,anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wastingin frail elderly; skin cancer and cancer cachexia; endometriosis,uterine bleeding, sexual dysfunction, erectile dysfunction and decreasedsexual response in females; organ transplant rejection, ischemia andreperfusion injury, wounding and spinal cord injury, and weight loss dueto a medical procedure selected from the group consisting ofchemotherapy, radiation therapy, temporary or permanent immobilizationand dialysis; hemorrhagic shock, cardiogenic shock, hypovolemic shock,cardiovascular disorders and cardiac cachexia; acute respiratorydistress syndrome, pulmonary fibrosis, chronic obstructive pulmonarydisease and asthma; enhanced immune tolerance; allergies; psoriasis,skin pigmentation depletion, acne and keloid formation; anxiety,depression, memory dysfunction and neuropathic pain; and renal cachexiaand natriuresis.
 19. A method according to claim 18, wherein obesity istreated.
 20. A method according to claim 18, wherein a feeding disorderis treated.
 21. A method of decreasing appetite according to claim 18.22. A method according to claim 21, whereincyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂, (SEQ IDNO:1) or a pharmaceutically acceptable salt thereof is administered. 23.A method according to claim 21,wherein-cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂,(SEQ ID NO:11) or a pharmaceutically acceptable salt thereof isadministered.
 24. A method of decreasing body weight according to claim18
 25. A method according to claim 24, whereincyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂, (SEQ IDNO:1) or a pharmaceutically acceptable salt thereof is administered. 26.A method according to claim 24, whereincyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂, (SEQ IDNO:11) or a pharmaceutically acceptable salt thereof is administered.27. A method of decreasing appetite and body weight according to claim18.
 28. A method according to claim 27, whereincyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂, (SEQ IDNO:1) or a pharmaceutically acceptable salt thereof is administered. 29.A method according to claim 27, whereincyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂, (SEQ IDNO:11) or a pharmaceutically acceptable salt thereof is administered.30. A method according to claim 18, wherein anorexia is treated.
 31. Amethod according to claim 18, wherein bulimia is treated.
 32. A methodaccording to claim 18, wherein AIDS wasting or wasting in frail elderlyis treated.
 33. A method according to claim 18, wherein cachexia orcancer cachexia is treated.
 34. A method of modulating ovarian weight,placental development, prolactin secretion, FSH secretion, intrauterinefetal growth, parturition, spermatogenesis, thyroxin release,aldosterone synthesis and release, body temperature, blood pressure,heart rate, vascular tone, brain blood flow, blood glucose levels, sebumsecretion, pheromone secretion, motivation, learning and behavior, painperception, neuroprotection, nerve growth, bone metabolism, boneformation and bone development by eliciting an agonist or antagonisteffect from a melanocortin receptor according to claim
 14. 35. A methodof inhibiting alcohol consumption, reducing alcohol consumption,treating alcoholism, or treating alcohol abuse by eliciting an agonistor antagonist effect from a melanocortin receptor according to claim 14.36. The use of a therapeutically effective amount of a melanocortin-4receptor agonist or antagonist according to any one of claims 1 to 6, ora pharmaceutically acceptable salt thereof, for the manufacture of amedicament useful to treat a disease or condition selected from thegroup consisting of: general inflammation, inflammatory bowel disease,brain inflammation, sepsis and septic shock; rheumatoid arthritis, goutyarthritis and multiple sclerosis; a metabolic disease or medicalcondition accompanied by weight gain, obesity, feeding disorders andPrader-Willi Syndrome; a metabolic disease or medical conditionaccompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia,cancer cachexia and wasting in frail elderly; skin cancer and cancercachexia; endometriosis, uterine bleeding, sexual dysfunction, erectiledysfunction and decreased sexual response in females; organ transplantrejection, ischemia and reperfusion injury, wounding and spinal cordinjury, and weight loss due to a medical procedure selected from thegroup consisting of chemotherapy, radiation therapy, temporary orpermanent immobilization and dialysis; hemorrhagic shock, cardiogenicshock, hypovolemic shock, cardiovascular disorders and cardiac cachexia;acute respiratory distress syndrome, pulmonary fibrosis, chronicobstructive pulmonary disease and asthma; enhanced immune tolerance;allergies; psoriasis, skin pigmentation depletion, acne and keloidformation; anxiety, depression, memory dysfunction and neuropathic pain;and renal cachexia and natriuresis.
 37. The use of the medicamentaccording to claim 36 to decrease appetite wherein said medicamentcomprisesHydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:42) or a pharmaceutically acceptable salt thereof.
 38. Theuse of the medicament according to claim 36 to decrease appetite whereinsaid medicament comprisesHydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:13) or a pharmaceutically acceptable salt thereof.
 39. The use ofthe medicament according to claim 36 to decrease body weight whereinsaid medicament comprisesHydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:42) or a pharmaceutically acceptable salt thereof.
 40. Theuse of the medicament according to claim 36 to decrease body weightwherein said medicament comprisesHydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:13) or a pharmaceutically acceptable salt thereof.
 41. The use ofthe medicament according to claim 36 to decrease appetite and decreasebody weight wherein said medicament comprisesHydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;(SEQ ID NO:42) or a pharmaceutically acceptable salt thereof.
 42. Theuse of the medicament according to claim 36 to decrease appetite anddecrease body weight wherein said medicament comprisesHydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQID NO:13) or a pharmaceutically acceptable salt thereof.
 43. The use ofa therapeutically effective amount of a melanocortin-4 receptor agonistor antagonist according to any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament useful to modulate ovarian weight, placental development,prolactin secretion, FSH secretion, intrauterine fetal growth,parturition, spermatogenesis, thyroxin release, aldosterone synthesisand release, body temperature, blood pressure, heart rate, vasculartone, brain blood flow, blood glucose levels, sebum secretion, pheromonesecretion, motivation, learning and behavior, pain perception,neuroprotection, nerve growth, bone metabolism, bone formation and bonedevelopment.
 44. The use of a therapeutically effective amount of amelanocortin-4 receptor agonist or antagonist according to any one ofclaims 1 to 6, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament useful to inhibit alcohol consumption,reduce alcohol consumption, treat alcoholism, or treat alcohol abuse.45. A compound of the formula:

or a pharmaceutically acceptable salt thereof.
 46. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 45 and a pharmaceutically acceptable carrier ordiluent; or a pharmaceutically acceptable salt thereof.
 47. A method ofeliciting an agonist or antagonist effect from a melanocortin receptorin a subject in need thereof which comprises administering to saidsubject a therapeutically effective amount of a compound according toclaim 45, or a pharmaceutically acceptable salt thereof.
 48. A method oftreating a disease or medical condition by eliciting an agonist orantagonist effect from a melanocortin receptor according to claim 45,wherein said disease or condition is selected from the group consistingof an acute or chronic inflammatory disease or medical condition,general inflammation, inflammatory bowel disease, brain inflammation,sepsis and septic shock; an autoimmune disease or medical condition,rheumatoid arthritis, gouty arthritis and multiple sclerosis; ametabolic disease or medical condition accompanied by weight gain,obesity, feeding disorders and Prader-Willi Syndrome; a metabolicdisease or medical condition accompanied by weight loss, anorexia,bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frailelderly; a neoplastic disease or medical condition, skin cancer andcancer cachexia; a reproductive or sexual medical condition,endometriosis, uterine bleeding, sexual dysfunction, erectiledysfunction and decreased sexual response in females; a disease ormedical condition resulting from treatment or insult to an organism,organ transplant rejection, ischemia and reperfusion injury, woundingand spinal cord injury, and weight loss due to a medical procedureselected from the group consisting of chemotherapy, radiation therapy,temporary or permanent immobilization and dialysis; a cardiovasculardisease or medical condition, hemorrhagic shock, cardiogenic shock,hypovolemic shock, cardiovascular disorders and cardiac cachexia; apulmonary disease or medical condition, acute respiratory distresssyndrome, pulmonary fibrosis, chronic obstructive pulmonary disease andasthma; enhanced immune tolerance; allergies; a dermatological diseaseor medical condition, psoriasis, skin pigmentation depletion, acne andkeloid formation; a behavioral or central nervous system or neuronaldisease or medical condition, anxiety, depression, memory dysfunctionand neuropathic pain; and a renal disease or medical condition, renalcachexia and natriuresis.
 49. A method of modulating ovarian weight,placental development, prolactin secretion, FSH secretion, intrauterinefetal growth, parturition, spermatogenesis, thyroxin release,aldosterone synthesis and release, body temperature, blood pressure,heart rate, vascular tone, brain blood flow, blood glucose levels, sebumsecretion, pheromone secretion, motivation, learning and behavior, painperception, neuroprotection, nerve growth, bone metabolism, boneformation and bone development by eliciting an agonist or antagonisteffect from a melanocortin receptor according to claim
 45. 50. A methodof inhibiting alcohol consumption, reducing alcohol consumption,treating alcoholism, or treating alcohol abuse by eliciting an agonistor antagonist effect from a melanocortin receptor according to claim 45.